Microneedle-aided nanotherapeutics delivery and nanosensor intervention in advanced tissue regeneration

Abstract

Microneedles (MNs) have been extensively used as transdermal therapeutics delivery devices since 1998 due to their capacity to penetrate physiological barriers with minimal invasiveness. Recent advances demonstrate the potential of MNs in improving diverse tissue regeneration when integrated with nanometer-sized therapeutics or sensors. This synergistic strategy can enhance drug delivery efficiency and therapeutic outcomes, and enable precise and personalized therapies through real-time monitoring of the repair process. In this review, we discuss how optimized MNs (through adjustments in geometry, material properties, and modular structure), when combined with dimension- and composition-specific nanomaterials, enhance tissue regeneration efficiency. Moreover, integrating stimuli-responsive nanotherapeutics or nanosensors into MNs for spatiotemporal-controlled and targeted drug release, physiotherapy effects, and intelligent monitoring is systematically outlined. Furthermore, we summarize therapeutic applications of nanotherapeutics-MN platforms in various soft and hard tissues, including skin, hair follicles (HF), cornea, joint, tendons, sciatic nerves, spinal cord, periodontium, oral mucosa, myocardium, endometrium, bone and intervertebral discs (IVD). Notably, recent attempts using nanosensor-MN platforms as smart wearable devices for monitoring damaged tissues via interstitial fluid (ISF) extraction and biomarker sensing are analyzed. This review potentially provides tissue regeneration practitioners/researchers with a cross-disciplinary perspective and inspiration.

Graphical abstract

Introduction

Tissue damage resulting from mechanical trauma and pathological conditions poses a significant global healthcare challenge and generates substantial clinical and socioeconomic burden [1]. While the human body possesses self-repair capabilities, it is limited and insufficient for large-scale injuries, severe and persistent infections, or conditions exacerbated by systemic comorbidities such as diabetes or immunodeficiency [2, 3]. Therefore, medical interventions are often necessary to improve the structural and functional restoration of damaged tissues [4]. Conventional therapeutic approaches, including oral and injectable drugs, autologous or allogeneic transplants, hydrogels, and tissue engineering scaffolds, are limited by several inherent shortcomings, such as first-pass metabolism, poor patient compliance, donor shortages, immune rejection, poor tissue penetration, and potential secondary injury. These challenges cause the urgent need for innovative and advanced strategies that can overcome diverse biological barriers and precisely modulate the complex and dynamic tissue regeneration microenvironment [5].

Over the past two decades, MNs have served as functional platforms to stably encapsulate diverse therapeutic agents and effectively deliver them into both soft and hard tissues [6]. A typical MN patch contains three essential parts: micron-height needle tips, a backing layer, and their junction. In the regeneration field, the needle tips can penetrate critical physiological barriers (stratum corneum, corneal barrier, blood-brain barrier, scar tissue) and bypass physical barriers (exudate, thrombi, bacterial biofilms), while painlessly generating micro-wounds on the tissue surface to trigger collagen remodeling, local stress alteration, and vascularization [7,8,9]. Securing these MN patches in diverse damaged tissues is critical to release therapeutic agents in precise, targeted, controlled, rapid, sustained, or intermittent manners. This process is determined by MN design parameters and the manufacturing materials’ physicochemical properties [10, 11]. The backing layer can be designed as stretchable, one-sided/wet adhesive, or peelable to avoid detachment and unwanted adhesion. It also can prevent serious infection by sealing the injured sites [7, 12]. Additionally, optimizing the junction between the tips and the backing layer can further improve transdermal delivery efficiency. In conclusion, optimizating MNs can achieve remarkable tissue regeneration by improving the efficiency of transdermal drug delivery and suitability for various damaged tissues [13].

The types of cells involved in tissue repair and regeneration are complex, their populations and microenvironments undergo dynamic changes across different stages. This necessitates therapeutics and sensors with stability, intelligence, and multifunctionality. Due to size, quantum and surface effects, nanomaterials exhibit enhanced cell targeting and permeation, catalytic ability, stimulus responsiveness, immune evasion, and special optical properties [14, 15]. Based on this, integrating nanomaterials with MNs to construct comprehensive in situ platforms offers a promising strategy to advanced tissue regeneration.

In recent years, the synergy of nanomedicine and MN technology has provided a promising strategy for tissue regeneration. Specifically, nanotherapeutics-loaded MNs perform multiple biofunctions such as antibacterial, anti-inflammatory, antioxidant, vascularization simultaneously [16, 17]. These platforms enable intelligent, effective or programmable delivery of nanotherapeutics to regulate immune, epithelial, endothelial, and stem cells during distinct regenerative phases [18, 19]. Besides, nanosensor-integrated MNs can serve as smart wearable devices to manage damaged tissues. These MN-assisted nanosensor interventions facilitate early diagnosis and timely treatment adjustment by real-time sensing biomarkers in ISF. Notably, integrating therapeutic and diagnostic components into a single MN platform enables the construction of closed-loop healthcare systems, merging precision medicine and personalized therapy in regenerative medicine [20].

As shown in Fig. 1, this review analyzes advances in nanotherapeutics-MN and nanosensor-MN platforms for improving tissue regeneration. Innovative optimization strategies for MNs and nanomaterials are systematically summarized. We outline the therapeutic applications of nanotherapeutics-MN platforms in diverse damaged tissues. The promising potential of nanosensor-MN platforms in biomarker sensing and regeneration monitoring is also highlighted. Finally, we discuss the challenges and future perspectives of MN-assisted nanotherapeutics delivery and nanosensor intervention in the fields of nanomedicine and regenerative medicine.

Fig. 1

Schematic illustration of selecting ideal nanotherapeutics and nanosensors to fulfill therapeutic and sensing roles in tissue regeneration with the assist of optimized microneedles. Created with BioRender.com

Optimizing MNs and nanomaterials for tissue adaptability and multifunctionality

Refinements of MN patches

The MN patch comprises needle tips, a backing layer, and junction. Through optimization of geometric parameters and physicochemical properties, selection of appropriate types and manufacturing materials, and implementation of modular design strategies, nanomaterial-integrated MNs can securely adhere to diverse tissue surfaces and significantly enhance tissue regeneration.

Optimizting MNs’ geometric parameters

Employing biomimetic strategies to design needle tips into unique shapes can increase friction between MNs with damaged tissues to achieve interlock, such as barb-like and pagoda shapes inspired by bee stings and porcupine quills, and grooved and slanted shapes inspired by crab claws and shark teeth (Fig. 2A) [21,22,23]. However, for electrochemical MN sensors, such increased friction may destroy their conductive coating. To avoid this risk, needle tips with micro-cavities have been developed (Fig. 2A) [24]. Compared to these MNs with uniform geometry, nonlinear MNs with variable needle height designs can elude the “bed of nails” effect that affects tissue penetration [25]. In addition, nonlinear MNs enable multi-target drug delivery [26].

MNs are prone to fracture and detachment when applied to tissues that move frequently or have uneven surfaces. Optimizing backing layers can also address these challenges. For example, MNs with kirigami-shaped and stretchable backing were applied to joints with complex motion [27]. Additionally, using near-infrared (NIR) light to control the bending and unfolding of a flexible polyvinyl alcohol (PVA) backing layer containing graphene oxide (GO) can enable MNs to adhere firmly to curved myocardial surfaces, thereby facilitating sustained vascular endothelial growth factor (VEGF) delivery [28].

For internal tissues or inaccessible anatomical regions, administering MNs in situ at these damaged site presents challenges compared to the more direct transdermal drug delivery. Backing layers were designed as tubular, rolled and balloon-catheter shapes to better match the anatomical structure of tissues (Fig. 2B) [29]. To minimize damage caused by MN administration and removal, inspired by pufferfishes, Zhang et al. designed MNs that concealed their sharp tips within the backing during vascular entry. Upon inflation, the tips popped out to penetrate the blood vessel wall. Subsequent NIR light irradiation triggered dissolution of the exposed tips, restoring a smooth surface for safe removal with minimal trauma (Fig. 2B) [30]. For other internal organs such as intestines with wrinkled surfaces, researchers developed orally administrable MNs featuring hollow shell-like backings. By shifting their gravity center to the tips to achieve vertical intestinal penetration without external forces like magnets (Fig. 2B) [31]. Notably, physiological fluid washout leads to unstable attachment of MNs to tissues with wet surfaces such as endometrium, requiring both needle tips and backing layers to be wet-adhesive [32]. Similar to application to hairy tissues, such adhesion should be reversible to prevent secondary injury when removed.

The junction between the needle tips and the backing layer can be optimized to prepare detachable MNs and ultra-fast acting MNs. For example, researchers introduced effervescent tablet components NaHCO₃ and citric acid into the junction, CO₂ was generated to promote drugs fast and deep release when needle tips were inserted into the tissues [33].

Selecting appropriate MN types

Different types of MN have their own advantages and disadvantages due to distinctive manufacturing materials and release mechanisms. For specific tissue damage, researchers need select the ideal MN type.

Upon contact with ISF, dissolving microneedles (DMNs) prepared from water-soluble polymers including hyaluronic acid (HA), gelatin (Gel), PVA, polyvinyl pyrrolidone (PVP), γ-polyglutamic acid (γ-PGA), carboxymethylcellulose sodium (CMC-Na) and chitosan (CS) can dissolve and release nanotherapeutics rapidly, thus facilitating deep tissue penetration without long-time attachment and frequent administration. As demonstrated by Zhang and coworkers, HA MNs were employed to deliver drug-encapsulated liposomes (Lipo) for androgenetic alopecia (AGA). The tips completely dissolved within 5 min, while Lipos exhibited sustained drug release [34].

In contrast to DMNs, hydrogel MNs release nanotherapeutics relatively slowly. Their swelling and shrinking properties facilitate exudate absorption and controlled drug release during treatment, while enabling real-time tissue monitoring via ISF absorption. Their high water content and excellent biocompatibility also ensure prolonged adherence to tissue surfaces without causing irritation. Common fabrication materials include gelatin methacryloyl (GelMA), hyaluronic acid methacryloyl (HAMA), PVA and silk fibroin methacryloyl (SilMA). Adding nanomaterials, copolymers and ions, the cross-linking degree and mechanical strength of hydrogel tips can be regulated, enabling MNs to match different tissue hardness and release drugs intelligently. For instance, Zhang’s team pretreated PVA tips with Na₂SO₄ to increase stiffness for piercing tissues and then softened the tips by adding Fe(NO₃)₃ to release exosomes (Exo) [35].

Compared to DMNs and hydrogel MNs, coated MNs are limited in drug loading dose. However, coatings can be easily sprayed onto tips and rapidly exert therapeutic or sensing functions. Lu and colleagues employed the Langmuir-Blodgett technique as a universal and rapid strategy to prepare antibacterial coated MNs. They achieved uniform coverage of zinc oxide (ZnO), silicon dioxide (SiO₂), and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) on poly(lactic-co-glycolic acid) (PLGA) MNs using only water and alcohol [36].

Solid MNs, renowned for excellent mechanical strength and stability, are widely used to hard tissues and stimulate collagen production. To further contain other therapeutic ingredients, MNs with internal cavities, called hollow MNs, offer a solution. Recently, Liu et al. invented 3D printed polycaprolactone (PCL) MNs and subsequently filled their cavities with heparin hydrogel which could absorb exudates and change color to visualize wound infections and release antibiotics smartly [37]. In addition to vacuum freeze-drying and heat-drying, freezing can also be used to accelerate MNs shaping and enhance their mechanical strength. Above all, such cryo-MNs can maintain the stability of bioactive nanotherapeutics such as microRNA (miRNA) and Exo [38].

Designing MNs as modular structures

The tissue regeneration process is complex, coherent and dynamic, with distinct therapeutic requirements across different phases. Adding components with variable functions into tiny tips presents a challenge. Although multifunctional nanomaterials can reduce the quantities of components required, MNs with modular structures can further enhance regenerative efficacy. The modular design includes the arrangement of individual tips into shell-core and layered forms, as well as the functional zoning of all tip arrays. For example, the MN tip, designed by Lyn and colleagues, comprised a hydrophilic shell and a hydrophobic core. The shell rapidly released mangiferin for early-stage anti-inflammation and the core slowly released Exo for late-stage angiogenesis and epithelialization (Fig. 2C) [39]. Although the shell-core structure can enable MNs to cause different repair events at different time, the shell influenced the core significantly. Tips with upper and lower layers not only enable MNs to release different nanodrugs simultaneously, but also facilitate targeted treatments according to tissue vertical spatial layering. For instance, Zeng’s group developed double-layered MNs, comprising one layer of glucose oxidase (GOx) and another of Arginine@ZIF-8 NPs. They can deplete glucose in wounds, while sustained release NO (Fig. 2C) [40]. Interestingly, researchers constructed voltaic cell-mimetic MNs by dividing all needle arrays into positive and negative electrodes, while adding conductive polypyrrole (PPy) to the MN backing layers. The cascade reaction of enzymes enabled MNs to continuously generate electrons for nerve repair (Fig. 2C) [41]. Due to needle tips with different heights and diameters degrade at different rates, introducting nonlinear parametric design in MNs allows the construction of multiple drug release modules in a single MN patch. For example, Sarabi et al. developed the MN with needle tips arranged in mountain and wave shapes to achieve programmable drug release in a single administration [26].

Fig. 2

Optimized design strategiess for microneedles in tissue regeneration. (A) Barb-like (a), pagoda-shaped (b), crab claw-like (c) and with micro-cavities needle tips (d) [21,22,23,24]. Copyright 2022, Elsevier. Copyright 2023, Elsevier. Copyright 2023, Wiley-VCH. Copyright 2024, American Chemical Society. (B) Tubular (b), ballooning (b) and hemispherical (c) backing layers [29,30,31]. Copyright 2024, Elsevier. Copyright 2022, Wiley‐VCH. Copyright 2023, Wiley‐VCH. (C) The MNs are designed as the modular structures with shell and core (a), layering (b) and array zoning (c) [39,40,41]. Copyright 2024, Royal Society of Chemistry. Copyright 2024, Elsevier. Copyright 2023, Wiley‐VCH

Nanomaterial options: dimension and composition

Different dimensional nanomaterials

Nanomaterials with different dimensions, classified as 0-dimensional (0D), 1-dimensional (1D), 2-dimensional (2D) and 3-dimensional (3D), exhibit distinctive physicochemical properties particularly quantum and surface effects. When delivered by MNs, they favour adsorption, catalysis and sensing functions in tissue repair.

0D nanomaterials, including quantum dots (QDs), nano-particles and nanoclusters, have large specific surface area and numerous active sites, so they can function as nanozymes to catalyze biological reactions in tissue microenvironment. These nanomaterials require surface modification and dispersants to prevent aggregation due to their high surface energy. For example, researchers electrostatic assembled negatively charged MnO₂ NPs with the positively charged antimicrobial peptides (AMPs) form electrically neutral and stable M@C NPs, that can act as photothermal nanozymes and were incorporated into GelMA MNs to further accelerate wound healing (Fig. 3A) [42]. Additionally, they have unique electronic and optical properties because their electrons and holes are confined in three dimensions. For monitoring wound, introducing carbon QDs enables fluorescence response in the pH range of 4 to 9 [43].

Owing to the high aspect ratio, 1D nanomaterials including carbon nanotube (CNT), nanofiber (NF), nanowire (NW) and nanorod (NR) are known for their considerable mechanical strength, high electrical and thermal conductivity. CNTs are often added into MNs to enhance hardness and coated MN sensors to transfer electrons.Their highly ordered microstructure can also promote the directed and organized growth of fibroblasts when added into backing layers [44]. Similarly, electrospun NFs can imitate the extracellular matrix (ECM) to provide a framework for cellular growth when integrated into MNs [45]. For example, Fu et al. used Fe-IDA NWs with viscosity and porous structure as the MN coating, which can not only co-delivery drugs but also exert enzymatic activity for infectious wounds (Fig. 3B) [46]. Notably, some 1D nanomaterials like Au NRs exhibit localized surface plasmon resonance effects. Based on this, Gong’s team constructed Cu²⁺-doped Zn₂GeO₄ persistent luminescence NRs and added them into PVA MNs. Without repeated photoexcitation, these MNs can constantly produce reactive oxygen species (ROS) for sustained antibacterial treatment [47].

2D nanomaterials such as GO, MXene, and transition metal dichalcogenides (MoS₂, TiS₂) are typically in the form of thin sheets. Their synthesis strategies include top-down exfoliation methods (mechanical, liquid phase, and chemical etching) and bottom-up self-assembly techniques (vapour deposition, hydrothermal, and sol-gel method). Notably, ultra-thin nanosheets (NS) with sharp edges can puncture biofilms to inhibit bacterial growth, and their abundant surface active sites facilitate bonding with other therapeutic agents. Based on this, Gan et al. added GOx onto the surface of MXene, aiming to promote catalysis and antibacterial by inducing mild hyperthermia. Adding them into γ-PGA MNs can improve the mechanical strength and disperse heat (Fig. 3C) [48]. Additionally, due to restricted electron movement, some 2D nanomaterials are optically transparent with over 97% light transmission to minimize the impact on vision during cornea regeneration [49].

Typical 3D nanomaterials include some metal-organic framework (MOF), porous silicon (pSi), nanoflower and tetrahedral framework nucleic acid (tFNA). Their hierarchical or interconnected network and framework structures make them porous, robust and stable. Hence, 3D nanomaterials often act as nanocarriers to load or selectively adsorb unstable constituents. For instance, PCN-224 can physically adsorb dimethyloxalylglycine (DMOG) to enable sustained release. With a single administration of HA MN, DMOG release can be sustained for up to 10 days, requiring only one-tenth the conventional antibiotic dose (Fig. 3D) [50]. pSi and nanoflowers are often selected for enzyme immobilization or function as nanoenzymes due to their numerous internal mesoporous channels and reactive surface sites [51, 52]. Additionally, 3D nanomaterials can act as nanocages to slowly release inorganic ions and organic ligands with therapeutic functions. Such as ZIF-67 prepared by Lu’s group slowly released Co²⁺ to increase the expression of hypoxia-inducible factor-1 (HIF-1) which protected vascular endothelial cells under ischemic and hypoxic conditions through MNs [53].

Fig. 3

Microneedles deliver different dimensional nanomaterials for tissue repair. (A) GelMA MNs can deliver 0D MnO₂ NPs to promote wound healing [42]. Copyright 2024, Elsevier. (B) Fe-IDA NWs adhere to MN for improved wound infection [46]. Copyright 2024, Wiley-VCH. (C) γ-PGA MNs encapsulating 2D nanomaterial MXene for wound treatment [48]. Copyright 2024, Elsevier. (D) 3D PCN-224 can sustain release DMOG after MN delivery [50]. Copyright 2023, Wiley‐VCH

Nanomaterials with different compositions

In terms of composition, nanomaterials can be classified into the following four categories: organic (lipid-based, polymer-based, polysaccharide-based), inorganic (metal-based, carbon-based, silicon-based), organic-inorganic hybrid (MOF and metal-phenolic network (MPN)) and bioactive (Exos, miRNA, small interfering RNA (siRNA) and tFNA) types.

Nanomaterial-MN as an intelligent stimulus-responsive platform

Nanomaterials can be integrated into MNs by hydrogen bonding, chemical bonding or electrostatic adsorption. The constructed nanomaterial-MN platforms can enhance tissue repair and regeneration through responsiveness to external stimuli or physiological condition changes.

External stimuli

Nanomaterial-MN platforms can respond to external stimuli including mechanical force, ultrasound, NIR, temperature, and magnetic field. Friction and movement in joints and IVD can trigger nanomaterial-MN platforms with triboelectric nanogenerators (TENG) to generate electrical stimulation (ES), which can promote drug release and modulate immunity (Fig. 4A) [27, 54]. Generally, interface and phase engineering allow nanomaterial-MN platforms to be ultrasound-responsive. For example, Xiang et al. added ZnTCPP@ZnO NPs with semiconductor-metal interface effect into MNs to enhance sonocatalytic efficiency for acne (Fig. 4B) [55]. Similarly, Wu et al. found that TiO₂ with the anatase-brookite phase exhibited better antibacterial efficacy, when delivered by HA MNs, in comparison to other crystal phases. This was attributed to minimized adsorption and activation energies for ROS production [56].

Some nanomaterials like QDs, black phosphorus (BP) NSs, MXene, PDA NPs, CuS NPs, GO, MnO₂, N3-4 F NPs, Prussian Blue (PB) NPs, Fe₃O₄ NPs and plasmonic Au/SiO₂ have photothermal conversion, when incorporated into MNs and under NIR irradiation, they can prevent bacterial growth and promote blood flow through photothermal therapy (PTT). Zeng and colleagues added PDA NPs into HAMA MNs and found that 40 °C was not only safe for Exo, but also accelerated angiogenesis by upregulating VEGF [57]. Additionally, by altering the state of MNs, NIR can function as a switch for drug release from MNs. For example, after 5 min irradiation, BP QDs can promote triamcinolone release by melting MNs (Fig. 4C) [58]. Although some nanomaterials and MNs can disperse heat, the intensity and duration of NIR must be limited as much as possible to avoid local overheating that could harm tissues.

External magnetic field intensity remain undiminished in living tissues, providing a heat-generating alternative to NIR for deep tissue repair. He and his coworkers designed a MN patch loaed with Fe₃O₄ NPs. By adjusting the distance between the MNs and the disc-type electromagnetic field generator Disk-ZVs, the magnetothermal therapy can be precisely focused on the needle tips to improve wound healing (Fig. 4D) [59]. In addition, changes in temperature can cause structural and morphological changes in MNs made of temperature-sensitive materials such as Gels, poly(N-isopropylacrylamide) (PNIPAm), HA and PVA. This design often affects the release of nanomaterials, mechanical strength of tips, peelability of the backing layer, and fixability of the MNs on the tissue surface (Fig. 4E) [60].

Fig. 4

As comprehensive platforms that respond to external stimuli. (A) Exercise self-powered triboelectric-responsive MN platform promotes EVs release to repair IVDD [54]. Copyright 2024, Nature Communications. (B) Ultrasound-responsive nanomaterials delivered by MNs for acne [55]. Copyright 2023, Science Advances. (C) NIR-sensitive nanomaterials can control drug release by controlling MN dissolution [58]. Copyright 2024, Wiley-VCH. (D) Using Fe₃O₄ NPs that respond to magnetic fields benefit skin regeneration [59]. Copyright 2023, Wiley‐VCH. (E) Temperature-sensitive hydrogel MN controls therapeutic agent release [60]. Copyright 2023, Science Advances

Physiological microenvironment

The microenvironment undergoes dynamic changes to regulate cell types and functions after tissue damage. Nanomaterial-MN platforms can respond to pH, enzymes, ROS, and glucose to regulate tissue repair precisely. By integrating CaCO₃, ZnO, ZIF-8, and micelles into MNs, pH-responsive platforms can be constructed. Lei and coworkers constructed pH-responsive micelles and added them into MNs. When applied to chronic wounds with acidic environments, the micelles released encapsulated AMPs as MNs dissolve [61]. Moreover, pH is a reliable indicator of damaged tissue, and monitoring it can reflect the state of recovery. As changes in pH affect the types and activity of repair enzymes in injured tissue, constructing enzyme-responsive MN platforms also becomes an advanced strategy to achieve precise treatment. HA and Gel can be degraded by hyaluronidase and gelatinase in damaged tissues, and they are often used as MN manufacturing materials to release multifunctional nanotherapeutics. For example, Yang’s group added Ce/Zn NPs to HA MNs, utilizing the enzyme sensitivity of HA to release Zn²⁺ and Ce^3+/4+ continuously [62].

Oxidative stress that generates large amounts of ROS is a common feature of various tissue damage. N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1, 3-diaminium (TSPBA) and thioketal (TK) are commonly introduced into hydrogel MNs or nanomaterials to construct ROS-responsive platforms. For example, Ding et al. prepared hydrogel MN with TSPBA, PVA, and HAMA, that could sense excessive ROS and release drugs accordingly [63]. Similarly, Liu et al. conjugated TK on the surface of FTL@SIN NPs and treated rheumatoid arthritis (RA) via polysaccharide MNs delivery [64]. Hyperglycemia often delay healing such as diabetic ulcers (DU). Introducing 4-amino-3-fluorophenylboronic acid (4-FPBA) and phenylboronic acid (PBA) into nanomaterial-MN platforms can achieve hypoglycemic, glucose-responsive drug release and monitoring [65, 66].

Treatments in damaged soft and hard tissues

Skin

The skin is the body’s largest organ and primary barrier against pathogen invasion, with a multi-layered structure that includes the epidermis, dermis, and subcutaneous layers. Severe damage to the skin may lead to systemic infections and even death. Common skin injuries can be categorized into four etiological types: microbial infections (infectious wounds and acne), disease-associated wounds (DUs, post-oncological wounds), physical trauma (mechanical injuries, radiation damage, burns, photoaging), and chemical harm (mustard gas-induced injuries). MNs synergize with multifunctional nanomaterials through adjustable penetration depth and release kinetics can achieve targeted and precise skin repair and regeneration. Key treatment strategies include antimicrobials, microbiota stabilization, anti-inflammation, antioxidation, angiogenesis, blood sugar regulation, O₂/NO/H₂ supply, iron metabolism modulation, collagen deposition and scar prevention.Due to continuous attack exogenous pathogens, open wounds often display chronic inflammation. Traditional antibacterial approaches aim to completely eliminate microorganisms from wounds, but recent research has highlighted the positive role of symbiotic microbiota in wound healing. Hence, striking a balance between harmful pathogens elimination and beneficial microorganisms protection is vital to restore the microecology of the wound surface. Qi and colleagues developed a core-shell MN that releases tannic acid (TA)-Mg NPs with ROS-clearing and antimicrobial properties on the infectious wounds within the first 48 h, and releases the core extracellular vesicles (EVs) extracted from probiotic to inhibit α-smooth muscle actin (α-SMA) expression and enhance microbial diversity in the later stages of repair (Fig. 5A) [67]. Notably, the accumulation of dead bacteria at the wound site risks exacerbating inflammation, necessitating their timely removal. Shan used the MgB₂ MN patch to trap and take away dead E. coli and Methicillin-resistant Staphylococcus aureus(MRSA) by binding to their lipopolysaccharide (LPS) and peptidoglycans [68]. In acne, excessive sebum clog skin pores and the resulting hypoxic environment favours the proliferation of P.acnes. MNs can physically puncture comedones, and the backing layer made of PVA and diatomaceous earth (DE) can absorb pus and bacterial debris [69].

DUs are severe complications of diabetes, where the hyperglycemic microenvironment at the wound exacerbates local hypoxia, affecting cell growth and metabolism. Compared to previously reported chlorella requiring photosynthesis and haemoglobin with limited O₂ release capacity, MN-aided nanomaterials can rapidly and stably generate O₂in situ. For example, Ran’s team developed the dual-module MNs that contain CaO₂ NPs to enhance miRNA-147 and deferoxamine (DFO) intracecellular delivery by producing O₂ bubbles, resulting in alleviation of hypoxia-induced apoptosis of human umbilical vein endothelial cells (HUVEC) (Fig. 5B) [70]. When consuming glucose, the cascading reaction between GOx and catalase (CAT) is also used to supply O₂. Shan and colleagues used MNs to deliver the Au-Cu₂MoS₄ NSs with NIR-II responsiveness and dual-nanozyme activity, aiming to alleviate the hyperglycemia and hypoxia on diabetic wound surfaces [71]. Additionally, activating the insulin signaling pathway to modulate macrophage polarization benefits diabetic wound healing. Yang et al. used protocatechualdehyde (PA) and Fe³⁺ to self-assemble NPF NPs with insulin-like effects, which were loaded into HA MNs to reduce the expression of insulin signaling pathway-related factors (IR, IRS-1, IRS-2, SHC) and regulate the transition of macrophages from M1 to M2 phenotype [72].

Recently, skin damage caused by highly toxic chemical agents has gained much attention. RNA-seq data have confirmed that mustard gas severely impair proliferation and differentiation of keratinocytes, leading to over expression of the miR-497-5p. Using MNs to deliver lipid NPs encapsulated with miR-497-5p inhibitors can alleviate epidermal dysfunction [73]. For post-tumor resection wounds, Lei and colleagues formed CINP@SiO₂ NPs to eradicate tumor cells by administering PTT. HA MNs can further disperse heat generated by these nanotherapeutics to prevent local overheating from hindering the skin regenerative process [74]. Treatment of UV-induced photoaging necessitates collagen regeneration to increase skin thickness. You and colleagues leveraged EVs from human dermal fibroblasts (HDFs) to encapsulate mRNA encoding COL1A1. With the assist of HA MNs, these nanotherapeutics were delivered to the dermis directly and evenly. After 28 days, the skin of the treated group revealed a significant reduction in the number and area of wrinkles, as well as an increase skin thickness (Fig. 5C) [75]. Additionally, skin damage consumes large amounts of NO, thus providing NO from external sources is also an effective strategy to promote skin regeneration. This can be achieved by adding NO donors such as L-Arg NPs to MN [40].

Burn wounds often have a thick eschar caused by necrotic tissue. MNs can penetrate them and sequentially deliver growth factors KGF-2 and aFGF to accelerate re-epithelialization. Sequential release can be achieved by mixing aFGF-encapsulated PLGA NPs with KGF-2, they were further incorporated into HAMA MNs to upregulate HIF-1α and Hsp 90 [76]. In cases of hypertrophic scars (HS) and keloids, MNs can physically disrupt disorganized collagen fibers while stimulating neocollagen formation, resulting in flatter and more elastic skin [77]. For instance, MNs delivered Exos encapsulating miR-141-3p, which enhanced targeting specificity, reduced HS thickness, realigned collagen fibers, and downregulated α-SMA, COL-1, FN, TGF-β2, and p-Smad2/3 expression [78]. The mechanical tension promotes scar formation by activating the YAP signaling pathway, therefore targeted inhibition of YAP or reducing wound tension can suppress scar formation. Wei and colleagues used silk fibroin methacryloyl (SFMA) MN to deliver Bi NSs and verteporfin (Vp). The YAP immunofluorescence staining after 90 days confirmed it can promote scarless healing [79]. Compared to normal dermal fibroblasts, myofibroblasts in HS contain higher levels of iron. Based on this, Zhao and colleagues designed GelMA MN containing AgNCs/TRG/ZIF-8 nanotherapeutics to induce ferroptosis in myofibroblasts by depleting glutathione (GSH) (Fig. 5D) [80]. Interestingly, compared to traditional linear MN patches with uniform needle lengths, researchers have innovatively developed nonlinear MNs to meet the treatment needs of all layers of damaged skin. This design integrates needles with varying heights within a single MN patch, which not only enables intermittent drug delivery but also facilitates simultaneous drug administration to different skin layers. Such a layered targeting design provides a novel approach to effectively promote skin regeneration (Fig. 5E) [26].

Fig. 5

Nanotherapeutics-integrated microneedles to treat various skin injuries. (A) CSMN@TA-Mg/LDEV can dynamically modulate the microecology at the wound site [67]. Copyright 2024, Wiley-VCH. (B) Dual-module MN generates O₂ and delivers miRNA-mDTC NPs and DFO for each stage of diabetic wound [70]. Copyright 2024, Wiley‐VCH. (C) The MN deliver COL1A1-EVs to improve photoaging skin [75]. Copyright 2023, Nature. (D) MN-mediated MOFs induce ferroptosis to treat HS [80]. Copyright 2023, Wiley‐VCH. (E) The nonlinear design of the MN arrays to treat skin diseases at varying skin depths [26]. Copyright 2024, Wiley‐VCH

Hair follicle

Abnormalities in the structure, growth cycle, and microenvironment of HFs may lead to serious hair loss, greatly affecting patients’ appearance and mental health. Traditional hair regeneration strategies may face some challenges including limited absorption, side effects such as skin irritation and reproductive issues related to minoxidil (MXD) and finasteride (FIN), high costs and infection risks associated with HF transplantation and platelet-rich plasma (PRP) injection, and limitations of low-level laser therapy due to specific indications [81].

The inherent mechanical stimulation of MNs can induce perifollicular angiogenesis to promote hair regrowth. Yuan et al. found that blank MNs could increase the expression of VEGF and a small amount of new hair growth in AGA mice after 14 days (Fig. 6A) [82]. In the nanotherapeutics-loaded MN platforms, MNs overcome the SC barrier initially, and nanocarriers enhance cellular uptake by dermal papilla cells (DPCs) of drugs such as FIN in inactive or closed HF. Cao et al. used glycerides and squalene, which are components of HF, to fabricate FIN-NLC-MNs, which demonstrated enhanced FIN skin retention and HF targeting delivery (Fig. 6B) [83]. Hair regeneration treatment requires long-term and frequent applications, which may impact patient compliance. To extend the duration of drug action, the sustained release properties of nanomaterials combined with the adhesion of MN patches provide an ideal solution. Additionally, the on-demand peeling design of MNs can reduce damage to HF and new hairs when removed. Liao et al. used DSPE-mPEG₂₀₀₀ to prepare MXD NPs with better stability and dispersion, and formed a temperature-responsive adhesive ring between tips and the backing layer of the MN. This design ensures robust adhesion of the patch for extended action time while allowing easy peeling above 45 °C (Fig. 6C) [84]. Exos derived from some stem cells such as the adipose-derived stem cells (ADSC) and human amniotic mesenchymal stem cells (hAMSC) have potential in regulating HF cycle when delivered by MNs. Hong et al. added hAMSC-Exos into MNs made of human hair-derived NPs and HA, enabling low-temperature yellow light (1900 K) to promote local blood circulation for hair regrowth [85]. Adjusting the porosity of PVA MNs can control the sustained release of these Exos [86].

To comprehensively treat HF miniaturization and abnormal HF cycle, MN-mediated nanotherapeutics can improve the perifollicular microenvironment by activating hair follicle stem cells (HFSCs), regulating hormones, supplying growth factors, reducing oxidative stress, and modulating immunity. Metal-based nanomaterials can not only act as nanozymes to reduce excessive ROS but also release metal ions (Zn, Cu, Ce, Si, etc.) necessary for HF regeneration. Hu et al. utilized DMNs to deliver PtNZs, enabling HFSC differentiation into outer root sheath (ORS) cells via ROS-scavenging and improvement of the HF microenvironment (Fig. 6D) [87]. However, normal cellular metabolism requires low doses of ROS to activate HFSCs and the Wnt-β-catenin signaling pathway. Bai and coworkers utilized MNs to deliver stoichiometric RED PDA NPs which can transport low doses of ROS to HFs directly and increase the expression of β-catenin for hair loss (Fig. 6D) [88]. In AGA, the production of dihydrotestosterone (DHT) may impair DPCs proliferation and differentiation. Zhang et al. employed MNs to deliver Cu/Zn co-doped mesoporous silica nanoparticles (ZC-MSN) encapsulating quercetin to protect DPCs from DHT by inhibiting 5α-reductase activity (Fig. 6E) [89]. Promoting the transition of HF from the telogen phase to the anagen phase is vital for hair growth. SFRP 2 is a HF cycle-related key regulatory protein. As reported, miR-218 can reduce its expression to regulate HF cycle. Zhao et al. used lipid-polymer hybrid nanoparticles (LPN) as nanocarriers to protect miR-218 from degradation. The MN/LPNs/miR-218 group showed a significant reduction in the telogen phase proportion of the HFs (Fig. 6F) [90].

Fig. 6

Unique optimization design of nanomaterial-loaded MN platforms for hair regrowth. (A) Blank MNs can improve perifollicular neovascularization [82]. Copyright 2022, Elsevier. (B) MN-assisted overcoming of the SC barrier, HF-targeting and penetration of lipid NPs [83]. Copyright 2020, Elsevier. (C) MNs with the switchable temperature-responsive ring can prolong MXD NPs action and be easily removed [84]. Copyright 2024, Elsevier. (D) DMN delivers PtNZs to treat AGA by scavenging ROS and promoting HFSC differentiation (a) [87]. Copyright 2024, Wiley-VCH. MN-aided PDA NPs function as low-dose ROS donors to realize controlled and efficient ROS intracellular delivery (b) [88]. Copyright 2024, Wiley‐VCH. (E) MN/LPN/miR-218 promote regeneration by regulating HF cycle [90]. Copyright 2022, Royal Society of Chemistry

Cornea

The cornea is a doom-shaped thin tissue with curvature, toughness, and elasticity, and its transparency and integrity are crucial for protecting eyeballs and maintaining visual function. Microbial infection, chemical burns, and physical injury may lead to improper healing of the epithelial and stromal layers and severe visual impairment [91]. Compared to traditional eye drops, ointments, in situ gels, and injections, MN platforms integrated with nanomaterials can avoid frequent application, high doses of antibiotics, low drug retention, and poor permeability caused by tear dilution, blinking, and corneal barrier in a minimally invasive manner.

The optical transparency of nanomaterials and MN manufacturing materials is crucial for cornea regeneration. Carbon-based nanomaterials with optical transparency and antimicrobial properties, such as imidazole-modified graphene QDs (IMZ-GQDs) and manganese oxide nanocluster-modified graphdiyne (MnOx/GDY) NSs, when delivered by PVP/PVA and HA/PMMA MNs showed a good light transmittance to treat corneal ulcers caused by infectious keratitis (Fig. 7A) [92, 93]. When designing MNs, compatibility with the cornea curvature is critical to avoid excessive tissue damage, uneven drug delivery, and poor targeting. To address MN tilting caused by the corneal curvature, Liu et al. developed an arc-shaped backing layer that mimics the eyeball’s natural shape, ensuring better alignment and more precise penetration (Fig. 7B) [94]. It is crucial to achieve a certain degree of rigidity in order to overcome the corneal barrier. After insertion, the nanomaterial-loaded MN patches can be softened in order to adapt to the internal soft tissue. Kong et al. employed freezing to enhance the mechanical strength of MNs made from RHCMA firstly. They then used NIR irradiation to trigger the nanozyme FeTAP NPs to produce heat, enhancing the antibacterial effects while softening the MNs to disperse heat (Fig. 7C) [95]. When MNs are applied to the cornea by traditional manual pressure, excessive or uneven force may cause secondary damage. Yu et al. used Nafion/PDA film as the backing layer of MNs, and triggered its contraction under NIR irradiation. Such MNs was inserted into rabbit corneas in a non-contact, spatially and temporally controllable manner. Besides, using a cross-shaped double film further increased the insertion pressure (Fig. 7D) [96]. MN patches for corneal regeneration sometimes need to be characterized by in vitro ocular kinetic tests to measure their retention time on the ocular surface [97].

In the damaged cornea, repeated microbial infections lead to excessive inflammation, causing matrix remodeling and ultimately making the cornea opaque. High levels of ROS exacerbate cellular damage and ocular hypoxia. Liu et al. constructed MGMN, which was spontaneously activated by POD, CAT, and SOD enzyme-like activities in the biofilm and inflammatory microenvironment. The SOD-CAT cascade reaction converted excess ROS into O₂ (Fig. 7E) [93]. Zhou et al. used iron-based MOF materials MIL-101 to encapsulate anti-inflammatory riboflavin NPs to construct MIL@riboflavin. Such nanotherapeutics are uniformly dispersed in SilMA MN patches to treat bacterial keratitis [98]. When the cornea is chemically burned, natural nanomaterials with a pH close to that of the human body, such as Exos, are a better choice. However, 95% of Exos are quickly eliminated on the corneal surface, MN-assisted delivery can increase their retention. Yu et al. modified the surface of ADSC-Exos with an anti-tumor necrosis factor-α antibody (aT) which can enhance cell targeting. MMP-9 released from the damaged cornea can break the peptide linker and promote aT release. PVA MNs are non-irritating to the ocular surface due to their high water content, and can assist the delivery of aT-Exos to promote the healing of alkali-burned mouse corneas (Fig. 7F) [99]. In summary, the integration of nanomaterials with MN systems represents a promising therapeutic strategy for corneal tissue regeneration (Fig. 7G).

Fig. 7

Representative applications of MN patches integrated with nanomaterials for corneal healing. (A) Images of rabbit eyes treated with IMZ-GQDs MN patches before and after fluorescein sodium staining (a). Photographs and SEM images of MGMN (b) [92, 93]. Copyright 2023, Elsevier. Copyright 2023, Wiley-VCH. (B) Flowchart of the MNs@Lido synthesis with a curved backing layer [94]. Copyright 2024, Elsevier. (C) The MN array can be reinforced by freezing and softened triggered by NIR irradiation [95]. Copyright 2023, Elsevier. (D) The MN with a light trigger mechanism for precise and programmable penetration [96]. Copyright 2023, Royal Society of Chemistry. (E) MNs loaded with nanozymes of MnOx/GDY facilitate corneal repair through multiple aspects [93]. Copyright 2023, Wiley‐VCH. (F) MN-assisted delivery of targeted-modified Exos for the healing of alkali burned cornea [99]. Copyright 2024, American Chemical Society. (G) A summary of optimization strategies for MNs integrated with nanomaterials to promote corneal regeneration. Created with BioRender.com

Bone, cartilage, tendon and IVD

Osteoarthritis (OA) and rheumatoid arthritis (RA) require long-term cartilage protection. To address the limitations of repeated joint injections and systemic drug dispersion from oral therapies, MNs loaded with nanotherapeutics enable targeted transdermal delivery or localized administration to damaged joints. This approach enhances drug retention at lesion sites while improving treatment precision. Inorganic nanomaterials such as gold nanorods with the aid of MNs can be used to treat RA by enhancing the penetration and action of drugs through external stimuli such as electroporation and PTT [100]. It is worth noting that joint movement involves frequent bending and stretching, which requires the backing layer of the MN to be stretchable and flexible. Inspired by paper-cutting, Li and colleagues designed a Kirigami-based TENG MN patch (KSM-TENG MN). This patch incorporated positive triboelectric materials (spider silk protein) and conductive nanomaterials (MXene) to ensure MN stretchability, while utilizing the conversion of mechanical energy into electricity to promote methotrexate (MTX) transdermal delivery (Fig. 8A) [27]. RA is a complex disease characterized by chronic synovial inflammation and joint cartilage erosion. Surface modification of nanocarriers can enhance the targeting of drugs to macrophages, chondrocytes, and fibroblast-like synovial cells (FLS). For example, Xia and colleagues enhanced the targeting of Cerium/Manganese oxide NPs to macrophages through BSA modification. These metal-based NPs not only possess antioxidant enzyme activity but also function as nanocarriers to encapsulate MTX. HA MNs can deliver them to mitigate their rapid clearance by macrophages in the circulatory system [101].

To address the limitations of traditional transdermal drug delivery in treating deep cartilage injuries, Lin’s team developed a solid MN with threaded grooves (ST MN). They used PLGA-PEG-PLGA nanoemulsions to encapsulate the mitochondrial repair protein PARKIN, while modifying the mitochondrial targeting molecule TPP on its surface. These constructed nanoetherapeutics were further embedded in the thermosensitive hydrogel and loaded into the MN grooves. With the aid of rigid ST MNs, these nanotherapeutics can overcome the cartilage matrix barrier and precisely localize to the mitochondria of damaged chondrocytes, demonstrating significant efficacy in alleviating OA (Fig. 8B) [102].

Tracheal cartilage reconstruction post-tumor resection requires site-specific chondrogenic differentiation of stem cells at the defect.Wang and colleagues encapsulated MnO₂/PDA@Cu NSs into a hydrogel MN made from matrix decellularized cartilage matrix modified with methacrylate. Under the photothermal effect, the NSs not only eradicate tumors but also promote angiogenesis, recruit stem cells, and promote their differentiation into cartilage [103].

The re-tear after rotator cuff repair is common. The resulting inadequate reconstruction of the tendon-bone interface (TBI) may lead to insufficient force transfer between the tendon and bone. Effective reconstruction of the fibrocartilage layer is essential to enhance healing and reduce this risk. Song et al. discovered that periodic melatonin can promote the expression of platelet factor 4 in ADSC-sEVs, promoting anti-inflammatory and the migration of bone marrow derived mesenchymal stem cells (BMSCs) to induce chondrogenesis. Their research also confirmed tendon-derived decellularized ECM (T-dECM) effectively upregulates tendon-related protein synthesis and gene expression in tendon-derived stem cells. Based on this, using the circadian rhythm-regulated sEVs (CR-sEVs) and T-dECM can construct a triphasic MN scaffold including a tip (HAMA and sodium alginate (SA)), stem ((CR-sEVs, HAMA, and SA), and base (T-dECM, HAMA, and SA). These MNs were applied to the tendon-bone junction to promote fibrocartilage regeneration and tendon repair (Fig. 8C) [104].

IVD is a hydrated fibrocartilaginous tissue consisting of the nucleus pulposus, annulus fibrosus (AF), and cartilage endplate. IVD degeneration (IVDD) caused by mechanical load, trauma, or aging can lead to lower back pain or disability, which attributes to ECM reduction, nucleus pulposus cell and AF cell damage, and a hypoxic and nutrient-deficient microenvironment [105]. The avascular structure and dense composition of the AF pose anatomical barriers that hinder effective drug delivery in treating IVDD. MNs with sufficient mechanical strength can penetrate the AF tissue and firmly anchor on its surface while preventing leakage of the nucleus pulposus inside. Hu et al. designed a threaded microneedle (T-MN) using SilMA and Laminin, incorporating BMSC-Exos loaded with miR-378 to regulate mitochondrial autophagy. Such T-MNs can increase friction to ensure stable fixation on the AF surface and sustained release Exos (Fig. 8E) [106]. MNs loaded with photothermal nanomaterials can “offend” the inflammatory microenvironment of the IVD, thereby alleviating inflammation. To achieve the “defense” mechanism, these MNs can generate heat to upregulate cytoprotective heat shock proteins (HSP). Based on this, Meng et al. added PDA NPs and the anti-inflammatory drug diclofenac sodium (DC) to GelMA MNs to prepare DCs/PDA/GelMA MNs. Under NIR irradiation, these MNs can generate heat to regulate DC release and scavenge ROS. This approach can upregulate HSP gene expression in AF cells, prevent mitochondrial dysfunction, reduce apoptosis, enhances ECM deposition, and ultimately restore nucleus pulposus integrity [107].

Fig. 8

MNs loaded with nanomaterials play a role in promoting regeneration within the musculoskeletal system. (A) MN patches inspired by paper-cutting for comprehensive joint management [27]. Copyright 2024, Elsevier. (B) Localization of lesion cells and targeted mitochondria in joints via MNs with helical structure for heat transfer [102]. Copyright 2023, Wiley-VCH. (C) Circadian rhythm-regulated EVs can promote the regeneration of fibrocartilage and the repair of tendons when applied to TBI via a triphasic MN scaffold [104]. Copyright 2024, Wiley‐VCH. (D) NVs encapsulating small molecule inhibitors are delivered by dual-barbed soluble MNs for the treatment of tendinopathy [108]. Copyright 2024, Wiley‐VCH. (E) T-MN can self-adhere to the AF, and deliver Exo@miR-378 for IVD repair [106]. Copyright 2024, Elsevier

Neural tissue

Neural tissues are delicate and prone to systemic dysfunctions after injury, and the axons exhibit extreme sensitivity to mechanical tension during regeneration. MN platforms enable in situ or transdermal delivery of nanotherapeutics to nerve injury sites and treat various neural regeneration disorders, including peripheral nerve injury (PNI), central nervous system injury (CNI), and neurodegenerative diseases. The treatment mechanisms involve neuronal regeneration, synaptic remodeling, axonal regrowth, and neural cell proliferation/differentiation.

The sciatic nerve, the longest peripheral nerve, controls lower limb sensation and motor function. Unlike traditional highly invasive treatments (e.g., surgical sutures, autologous nerve grafts), nanotherapeutics-loaded MNs are designed as conductive nerve guidance conduits (NGCs) to minimize nerve mechanical damage and enhance regeneration efficacy. These MN NGCs (MNGCs) can conduct or generate electrical stimulation (ES) to promote axonal regeneration and myelin formation. Instead of external power sources, constructing nanomaterial-based biofuel cells (BFCs) on MNs or integrating conductive and piezoelectric nanomaterials into MNs enables self-powered functionality. For example, Zhang et al. encapsulated GOx and horseradish peroxidase (HRP) in ZIF-8 to form ZG NPs and ZH NPs. The arrays in MNGCs were divided into anode and cathode sections, and loaded with ZG NPs and ZH NPs, respectively. The enzymatic cascade consumed blood glucose to generate electrons, and the PDA-modified PPy/PVA hydrogel backing layer completed the circuit. In rats, these biocompatible MNGCs were implanted into damaged sciatic nerves to promote regeneration (Fig. 9A) [41]. However, BFCs struggle to maintain stable long-term output of ES at the intensity required for PNI. To address it, Hu et al. incorporated piezoelectric ZnO NPs and conductive reduced graphene oxide (rGO) into PCL MNGCs. They can continuously convert easily generated mechanical energy into electrical energy needed for sciatic nerve regeneration. Furthermore, microchannels are created on the MNGC surfaces by 3D printing technology, aiming to guide Schwann cells directed proliferation [109]. However, excessive mechanical deformation in piezoelectric MNGCs may generate currents surpassing safe thresholds, causing “electrical overload” phenomena. Similar to the BFCs’ acidic metabolic byproducts like H₂O₂, “electrical overload” may induce oxidative stress and subsequent cell damage. In addition, implanted MNGCs face challenges in safe removal when ES is no longer required. To address these challenges, inspired by Chinese acupuncture, Liu et al. designed a MN with threaded grooves on the needle surface to improve PNI electrical therapy. On one hand, to minimize nerve cell damage caused by “electrical overload”, neuroprotective drugs (Vitamin B12/E) were co-encapsulated within liposomes, which then were added into hydrogel microspheres to achieve sustained drug release. On the other hand, to reduce the immune response and tissue damage triggered by MN insertion, the hydrogel containing nanotherapeutics was added to the threaded grooves to form the lubricating MN coating to reduce friction [110].

In the treatment of CNI, the blood-spinal cord barrier (BSCB) and blood-brain barrier (BBB) limit efficient drug delivery to the lesion site. For spinal cord injury (SCI), MN can help natural nanotherapeutics such as Exos to penetrate the spinal dura mater and pia mater, and deliver them to spinal lesion sites. Compared to traditional intravenous or intrathecal injections, such in situ delivery strategy can avoid repeated invasion and drug wastage, promoting axonal regeneration at the primary stage of SCI without secondary injuries. For example, Fang et al. fabricated a porous GelMA MN that matches the mechanical strength of the spinal cord. Through size-optimized pores, mesenchymal stem cell (MSC)-derived EVs can be sustainably released to intrathecal lesions. In the T10 contusion SCI models, anti-5-hydroxytryptamine/neurofilament immunofluorescence staining confirmed that axonal regeneration and extension towards the lesion site was significantly enhanced in the MN-MSC-treated group. The GelMA MNs can preserve MSC viability and release their EVs to the lesion site over 7 days, creating a good axonal regenerative microenvironment (Fig. 9B) [111]. However, the porous structure of these MNs exhibited limited mechanical strength (~ 10.77 kPa), which only matched that of the rat pia mater (~ 8.1 kPa). Therefore, careful dura incision was required before positioning them at the defect. To overcome the spinal dura barrier, Han et al. designed a GelMA MN patch loaded with 3D-cultured MSC-derived Exos, with a Young’s modulus of ~ 500 kPa, the MN’s mechanical properties match those of spinal tissue (200–600 kPa). Proteomic and transcriptomic analyses revealed 3D-Exos enhanced regulation of neurodevelopment, neuroinflammation, and cellular proliferation compared to 2D-Exos. After 28 days, GelMA hydrogel MN released 3D-Exos showed superior retention and nerve regeneration in SCI compared to direct injection [112]. In neurodegenerative disease therapy, MNs enable transdermal delivery of drug-loaded nanomaterials such as PLGA NPs into systemic circulation. Optimized NP physicochemical properties (size < 200 nm, PDI < 0.2, surface charge) facilitate subsequent BBB penetration. These NPs ultimately accumulate in brain parenchyma, upregulating synaptic remodeling and glial modulation proteins to promote neural repair [113].

Long-time retention of MNs with high mechanical strength may induce secondary injuries, primarily due to tension accumulation, which compromises regenerative microenvironments. To reduce these risks, MNs are often fabricated from biodegradable, modulus-tunable hydrogels such as GelMA, HAMA. Specifically, hydrogel MN ensures its initial stiffness during nerve penetration, softens on contact with fluids, and degrades simultaneously with tissue contraction during repair to prevent tension increase. Furthermore, hydrogels loaded with nanotherapeutics can serve as solid MNs’ coatings to reduce insertion friction and mitigate shear stress-induced axonal damage [114].

Oral mucosa and periodontal bone

When therapeutic agents are applied to the oral mucosa and periodontal tissues, their retention is often insufficient due to saliva dilution and chewing movements [115]. Current research has confirmed that, with the assistance of MNs, multifunctional nanotherapeutics can penetrate the periodontal tissues and oral mucosa, and remain fixed on their surface for an extended period to promote the regeneration of oral mucosa and alveolar bone. These MNs are typically made of highly hydratable and degradable materials such as HAMA, GelMA, γ-PGA and silk fibroin (SF). As shown in Table 1, for oral ulcers, incorporating nanotherapeutics like MOFs and Exos into MNs can effectively enhance antibacterial effects and modulate the inflammatory microenvironment, thereby promoting oral mucosa regeneration. Ge et al. added ZIF-8 NPs in the backing layer of SF MNs and loaded BMSCs-Exos into the needle tips, enabling LPS-triggered release to accelerate oral ulcer healing (Fig. 9C) [116]. In addition, as oral ulcers are often accompanied by pain, MNs such as HA MN can form a hydrated protective layer on the surface to alleviate pain.

Periodontitis may lead to the formation of periodontal pockets between periodontal tissues and teeth, where microorganisms colonize and exacerbate inflammation causing detachment and degeneration of the periodontium. MN can be inserted into the periodontal pocket and pierce the biofilm, and the loaded nanomaterials can achieve sustained antibacterial effects, anti-inflammation, and promote periodontal bone repair. For example, Chen and colleagues constructed an organic-inorganic hybrid nanoenzyme SF/CuS with POD-like activity and PTT properties. Under NIR irradiation, the HAMA MNs can transfer heat to deep tissues, and SF/CuS produced ROS and released Cu ions to achieve bactericidal effects, ultimately promoting periodontal bone growth and increasing bone mass (Fig. 9D) [117]. Other applications of nanotherapeutics-MN platforms for promoting periodontal bone regeneration are summarized in Table 1.

Table 1 The nanotherapeutics-MN platforms for advanced oral mucosa and periodontal bone regeneration

Endometrium

Damaged endometrial basal layer may lead to intrauterine adhesions and cause infertility. The repair mechanisms mainly involve antioxidantion, neovascularisation and smooth muscle regeneration, aiming to restore reproductive function. Due to the irregular and wet uterine environment, MNs were designed with Janus characteristics. For example, Wang et al. divided the backing layer into two layers with the outer layer made of HA to resist protein and cell adhesion, and the inner layer and needle tips made of Gel and GelMA to provide adhesive properties. Besides that, the needle tips were coated with a layer of poly-L-lysine to facilitate adhesion of the nanotherapeutics Exos (Fig. 9E) [123]. Under oxidative stress, a large amount of ROS is detrimental to the regeneration of smooth muscle cells and blood vessels. Using nanoenzymes can provide antioxidant effects to promote the morphological reconstruction of the endometrium. Zhu and colleagues mixed CeO₂ nanozymes into the backing layer of GelMA MNs loaded with stem cells. This approach significantly increased endometrial thickness by promoting the regeneration of abundant muscle bundles, thereby improving the pregnancy rate compared to the control group [124].

Cardiovascular tissue

Acute myocardial infarction (AMI) is typically caused by a sudden reduction or interruption of blood flow in the coronary arteries, leading to acute ischemia and necrosis of the myocardium. Myocardial ischemia-reperfusion injury (MIRI) occurs after blood flow has been restored causing even severe damage to the myocardium. When treating AMI, the focus is on anti-inflammatory and antioxidant stress; whereas for treating MIRI, the emphasis is on inhibiting fibrosis and promoting myocardial tissue regeneration. MN patches can reduce leakage incidents with myocardial injections affecting other tissues through the bloodstream. Wang and colleagues designed a double-layer MN patch suitable for the sequential treatment of AMI. The front end of the needle tip uses PVA hydrogel crosslinked with TSPBA to release CeO₂ NPs for eliminating excessive ROS and regulating inflammation. The end of the needle tip was loaded with MSNs of Cur and L-Arg, when triggered by ultrasound, which produced NO to regulate vascular function and prevent fibrosis [125]. Using MN to deliver miRNA encapsulated in nanomaterials is an efficient non-viral in vivo transfection method that can achieve a sustained release and lysosomal escape in the body. Chen and coworkers encapsulated miR-30d into ZIF-8 NPs and delivered them by HAMA MNs to alleviate MIRI, mainly by inhibiting the proliferation of cardiac fibroblasts and reducing the apoptosis of myocardial cells. Connexin 43 staining showed that adding of Au NPs to the MN could reconstruct electrical pulses in the infarcted myocardium under ultrasound triggering, thereby promoting the recovery of cardiac pumping function. miR-30d was stably retained in the myocardium for up to 3 weeks and gradually degraded within 6 weeks (Fig. 9F) [126]. Yuan and colleagues used UCMSC-Exos to encapsulate miR-29b mimic which could inhibit the TGF-β signaling pathway and ECM remodeling when delivered by MN [127]. Hu et al. encapsulated BMSCF with PLGA NPs to form BMSCFNPs and delivered by MNs with elastin-like peptides (ELPs). It was found that compared to cardiac fibroblasts, myocardial cells engulfed BMSCF-NPs more easily [128]. During myocardial tissue regeneration, directional growth can be achieved by conductive CNTs when they are integrated into the MN backing [129].

Fig. 9

Nanomaterial-loaded MNs treat damaged sciatic nerves, spinal cords, oral mucosa, periodontal tissue, endometrium, and myocardium. (A) MNGCs for sciatic nerve regeneration and muscle atrophy inhibition [41]. Copyright 2023. Wiley-VCH. (B) GelMA MN loaded with MSC-EVs for the treatment of SCI [111]. Copyright 2023. Nature. (C) SF MNs loaded with Exos and ZIF-8 are used for oral mucosa regeneration [116]. Copyright 2024. American Chemical Society. (D) MN patches loaded with SF/CuS nanozymes are used for antibacterial treatment of deep periodontal pockets and promotion of periodontal bone regeneration [117]. Copyright 2024. Elsevier. (E) MNs loaded with Exos and featuring Janus adhesion treat endometrial adhesion [123]. Copyright 2024, Royal Society of Chemistry. (F) A nanoparticle-laden patch for delivering miRNA to infarcted myocardium to alleviate MIRI [126]. Copyright 2024, American Chemical Society

Tissue-specific optimizations of MN-aided nanotherapeutics delivery: from soft to hard tissues, superficial to deep tissues

To maximize tissue regeneration efficacy, it is essential to tailor the design and administration methods of nanotherapeutics-loaded MNs platforms based on tissue-specific characteristics (both soft and hard tissues, superficial and deep tissues), which represents the future direction of regenerative biomaterials.

Skin is a typical soft tissue, and its flat surface and mechanical homogeneity make the delivery of nanotherapeutics via MN patches relatively simple and straightforward. In contrast, in situ MN application in articular cartilage, spinal cord, or IVD requires overcoming multiple rigid physiological barriers (e.g., cartilage matrix, dura mater, and annulus fibrosus), requiring higher mechanical strength of MNs [106, 116, 130, 131]. However, long-term retention of such rigid MNs may cause secondary injuries such as cerebrospinal fluid leakage or nucleus pulposus herniation. To address this challenge, two primary design strategies have emerged. The first involves using soluble MNs or coated MNs for rapid drug release, where the patch is removed, and nanotherapeutics exert long-term effects. The second focuses on designing stiffness-gradient or tunable MNs for heterogeneous tissues. For example, in treat of SCI, MNs can soften after penetrating the dura mater, aiming to protect the fragile neural tissue inside [132]. For IVD, MNs can be designed with a dual-module structure to simultaneously accommodate the differing mechanical properties of the annulus fibrosus (stiff) and nucleus pulposus (soft) [106].

In soft tissue applications (e.g., tendon and dermis), factors such as tissue tension, elasticity, and fiber alignment must be considered to minimize mechanical stress-induced scarring. Additionally, for mechanically sensitive tissues (e.g., nerves, myocardium), MN design requires precise control of mechanical parameters to avoid tissue surface tension accumulation, which hinders regeneration [133,134,135].

Beyond anatomical structure, the administration methodology of the MN patch should be further optimized based on the tissues’ position within the body. Compared to superficial tissues like skin and HFs, applying MN patches in situ to internal tissues (e.g., sciatic nerve, spinal cord, heart) is more challenging. Additional administration methods are used to aid MN platform in situ deliver nanotherapeutics to deeper tissues. For example, inspired by the anatomy of a snake’s jaw, Mei et al. developed a minimally invasive MN implantation platforms by combining MNs and a kidney stone retrieval device. These MNs can deliver MSC-derived Exos to the damaged heart tissue for cardiac repair without requiring open chest surgery [136].

For both deep and superficial tissues, securing MN patches on the tissue surface is critical for long-term treatment safety and precision. For tissues in frequently moving or wet environments (e.g., joints, cornea, uterus), the main optimization methods involve enhancing tissue adhesion, enabling needle tips to self-anchor, improving the backing layer’s flexibility and stretchability, and achieving better curvature matching to the target tissue [8, 137, 138]. Reversible tissue adhesion allows for safe MN removal when unnecessary [139]. Additionally, stimulus-responsive MN patches can be designed based on tissue composition, or modular designs (e.g., rapid-release and sustained-release combinations) can achieve programmed drug release, reducing the need for frequent patch replacement [140].

Transdermal delivery of nanotherapeutics via MNs serves as a universal strategy for regenerative therapy, but in situ delivery requires balancing practicality, safety, and tissue compatibility. Transdermal delivery should focus on optimizing targeting of nanotherapeutics, while in situ application must prioritize tissue adaptability of the MN platform. In summary, by synergistically optimizing nanotherapeutics-MN platforms design strategies and administration methodologies based on tissue anatomy, physiological microenvironment, kinetic behavior, and dynamic regeneration stages, safe and highly efficient tissue repair and regeneration can be achieved.

Smart wearable devices

During the process of tissue repair, dynamic changes occur in cellular metabolism and their microenvironment. Incorporating nanomaterials with MN platforms can monitor this process in real-time by extracting ISF and sensing biomarkers. Such real-time feedback enables healthcare workers to develop personalized treatment plans for patients. Notably, closed-loop therapy can be established in some nanomaterial-MN platforms. Currently, enzymes, ion-selective membranes and aptamers are primarily used to selectively capture target analytes in ISF. Using electrochemical sensors, fluorescent sensors, colorimetric sensors or surface-enhanced Raman scattering (SERS) techniques enable one-time detection or continuous real-time monitoring of biomarkers (Fig. 10A).

ISF extraction from tissues

Blood samples are widely used for disease diagnosis but often require complex preprocessing due to coagulation. Additionally, frequent blood draws may be unsuitable for many patients. In contrast, ISF is formed by the filtration of blood through capillaries and does not require preprocessing. It allows for repeated collection, provides a stable sample volume, and contains abundant biomarkers, making it a promising alternative to blood [141]. Certain inflammatory cytokines in ISF exhibit concentrations up to 40 times higher than in blood. For example, Li et al. employed solid MNs to collect 5 µL samples of both ISF and blood, demonstrating that simultaneous detection of five pro-inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α, and IP-10) was faster in ISF compared to blood [142]. Different types of MN (hollow MN, swellable MN, porous MN, coated MN, and dissolvable MN) extract ISF through semi-invasive principles like vacuum drive, polymer expansion, capillary action, and specific recognition. Xie et al. developed 3D-printed hollow MNs that could be connected to a vacuum tube via a flexible tube, generating negative pressure to extract approximately 18 µL of interstitial fluid (ISF) from a rabbit’s ear within 5 min [143]. However, this requires an external device to provide negative pressure. Mo et al. integrated a small suction cup on the back of the MN, enabling negative pressure generation through manual compression alone (Fig. 10B) [144]. For example, Ausri et al. developed a hydrogel MN with a porous structure and swelling properties by cross-linking dopamine-HA (DA-H) with tyrosine (Tyr) for β-hydroxybutyrate (β-HB) monitoring. The MNs achieved maximum swelling 30 min after skin insertion (Fig. 10C) [145]. It is noteworthy that the efficiency of swellable MNs in extracting ISF is also influenced by the molecular weight of the fabrication material. Wang et al. visualized the extraction of FITC-dextran by MeHA MNs, and demonstrated that MNs fabricated from HA with a molecular weight of 10–100 kDa exhibited higher protein extraction efficiency compared to those made from 200 to 400 kDa HA [146]. Incorporating nanomaterials into MNs not only improves their mechanical strength but also enables the fabrication of solid porous MNs that can passively and efficiently extract ISF via capillary action. For example, by pouring a solution mixed with SiO₂ NPs into a mold, SiO₂ NPs were removed by NaOH through chemical etching to create pores on the surface of the MN [147]. However, considering the potential risks of using strong alkali reagents, Pang et al. used a solution of cellulose acetate/DMSO containing SiO₂ NPs as the ink for 3D printing. When the printed MNs were immersed in water, phase separation occurred, creating a highly nanoporous surface structure. This design demonstrated remarkable ISF collection efficiency, extracting 3.3 mg within 1 min and 6.2 mg within 10 min, even on curved skin surfaces, enabling effective colorimetric analysis (Fig. 10D) [148].

Fig. 10

Hollow MN, porous MN, and hydrogel MN are utilized for the extraction of ISF. (A) Schematic diagram of the MN platform responsible for nanomaterials as a smart wearable device. Created with BioRender.com (B) The extraction of ISF using negative pressure [144]. Copyright 2022. Elsevier. (C) The characterization of hydrogel MN for sensing ketones includes the assessment of porosity and swelling ratio [145]. Copyright 2023, Wiley-VCH. (D) Utilizing SiO₂ NPs to create nano-scale pores on the MN surface for the extraction of ISF [148]. Copyright 2024, Wiley-VCH

Point-of-Care (POC) sensing platform

Biomarkers capture

Biomarkers related to tissue damage repair and regeneration status include metabolic products (glucose, ascorbic acid, ketones, lactate, and uric acid), oxidative stress indicators (ROS, GSH, inflammatory factors), hormones, electrolytes (Na⁺, K⁺, Ca²⁺, H⁺), nucleic acids (miRNA, DNA), enzymes (thrombin, kinase, Tyr), LPS and so on. The conventional method of extracting ISF for offline detection involves two separate steps, which prevents real-time tracking of tissue regeneration status. MNs loaded with nanomaterials can specifically capture biomarkers in ISF in situ through enzyme catalysis, ion-selective membranes, or aptamers. This integration enables direct integration with a POC sensing platform for rapid biomarker quantification and real-time diagnostic feedback at the patient’s bedside. Coated MNs enable biomarker detection in ISF through surface modification with conductive and catalytic materials, serving as the most widely employed working electrodes (WE) in electrochemical MN sensors. For example, Shukla’s team coated the surface of the MN electrode with siloxane ((3-aminopropyl) trimethoxysilane (APTMS) to produce an amino-terminal combined with the carboxyl group of glucose oxidase (GOx) and lactate oxidase (LOx) to form an amide bond to sense glucose and lactate [149]. Bai et al. developed a coin-sized glucose MN sensor using an organic electrochemical transistor (OECT). The hydrogel needle tip encapsulated GOx and was coated with Au NPs for enhanced conductivity. Such sensor showed a linear response to glucose concentrations from 10^-6 to 10^-1 M. Glucose oxidation generated electrons, which diffused passively to the OECT gate, where signal amplification improved the signal-to-noise ratio [150]. Based on the same principle, electrochemical MN sensors responsive to tyrosinase can also be prepared for identifying an early-stage melanoma specifically by modifying the WE surface with DA to facilitate electron transfer upon redox reactions [151]. In the detection of electrolyte balance, a liquid ion-selective membrane coated on the surface of the MN electrode allows specific ions to accumulate and generate current related to concentration. It is also possible to use a single MN patch to simultaneously monitor multiple ions to comprehensively assess the state of electrolytes. Zhu et al. successively deposited conductive polymer PEDOT-PSS and an ion-selective membrane on the surface of a MeHA MN to construct the WE and characterized it using cyclic voltammetry. They successfully detected Na⁺, K⁺, Ca²⁺, and pH values to rapidly diagnose electrolyte imbalances [152]. To prevent signal drift from conductive polymers in ion-selective sensors, researchers tested porous carbon nanomaterials as alternatives. They compared nonporous carbon particles (SPC), mesoporous carbon nanoparticles (MCN), and colloid-imprinted mesoporous carbon (CIM) for K⁺ and pH detection, evaluating their porosity and capacitance for stable performance [153]. Aptamers are single-stranded DNA or RNA with high affinity, and their conformational changes can be transformed into measurable signals. For instance, Bakhshandeh et al. coated MNs with L-lactate aptamers, creating a highly selective lactate sensor with a lifespan exceeding three days [154]. In addition, integrating aptamers as biorecognition elements into MNs can also develop immunocapturing MNs for capturing antigens and microorganisms [155].

Electrochemical sensing

Electrochemical MN sensors typically employ a three-electrode system which are WE, reference electrode (RE), and counter electrode (CE). The working principle involves converting chemical signals into electrical signals for detecting biomarker concentrations at trace levels. They are manufactured by MEMS, chemical etching, laser ablation, injection molding, and 3D printing. Metallic MNs possess inherent conductivity as WE, but for polymer MN electrodes with poor conductivity, nanomaterials such as metal NPs (Pd@Au NPs), CNTs, or graphene can be used to modify the WE through physical adsorption, chemical modification, or electrochemical deposition to produce an electroactive surface. These nanomaterials also enhance the mechanical strength of MNs and reduce background current [149]. The thickness of the coating is a key factor affecting the performance of electrochemical MN sensors. In addition, conductive polymers can be used to fill or modify hollow MNs which can also rapidly initiate drug treatment after diagnosis. For example, Huang et al. developed a glucose electrochemical sensor by coating hollow MNs with a Nafion solution incorporating single-walled carbon nanotubes (SWCNTs), alongside another solution containing GOx and an osmium redox mediator, which collectively functioned as the WE. The Nafion membrane enhanced enzyme stability and improved the signal-to-noise ratio, while the interconnected network of SWCNTs facilitated efficient electron transfer from GOx via the osmium mediator to the SWCNTs, thereby boosting glucose sensitivity. Moreover, the hollow MN design not only expands the interfacial contact area with ISF but also enables integrated insulin delivery, demonstrating a dual diagnostic-therapeutic functionality [156]. However, enzyme-based electrochemical sensors frequently suffer from signal drift, necessitating repeated recalibration and compromising long-term stability. In contrast, nanozymes have emerged as a promising non-enzymatic alternative due to their superior stability. For example, researchers developed a composite electrode by blending prussian blue (PB) with multi-walled carbon nanotubes (MWCNTs) into a paste, which was then applied to MN surfaces and thermally cured to form the WE. This configuration significantly enhanced electron transfer efficiency owing to its expansive active surface area. Once deposited, the PB NPs demonstrated nanozyme-like catalytic activity, enabling sensitive detection of H₂O₂ levels without enzymatic degradation concerns. This approach combines the robustness of nanozymes with the conductivity of carbon nanomaterials, offering improved reliability for continuous monitoring applications [157].

Fluorescent sensing

Many nanomaterials possess intrinsic fluorescent properties. When integrated into MN platforms, these fluorescent nanomaterials not only enable real-time in situ visualization of biomarkers within tissue, but also allow quantitative determination of biomarker levels in ISF through correlation between fluorescence intensity and target concentration. For instance, Liu et al. developed a PEGDA/Alginate hydrogel MN loaded with europium (Eu)-MOF for visual cortisol (CORT) monitoring. The hydrogel tips rapidly absorbed ~ 5 µL of ISF within 1 h, demonstrating efficient sampling. The Eu-MOF’s fluorescence decreased with increasing CORT levels due to quenching upon CORT binding. This system enables potential applications in monitoring stress and hormone-related skin conditions like acne [158]. However, this fluorescence quenching makes long-term monitoring difficult. Hu et al. constructed a Förster resonance energy transfer (FRET) hydrogel sensor. This fluorescence sensor consists of a fluorescence donor FAA, a fluorescence acceptor RhB, and PBA. Glucose binding alters the FAA-RhB distance, modulating FRET efficiency and RhB fluorescence, enabling 6-hour continuous monitoring [159]. To achieve longer fluorescence retention, Collins et al. encapsulated QDs into PMMA to form QD-PMMA spherical particles, and loaded them onto PVA MN. This MN can emit fluorescence under NIR irradiation for up to six months. They also cleverly utilized the NIR-triggered fluorescence characteristic to design MNs with patterns that protected patient privacy [160]. Fluorescence sensors can monitor therapeutic agent release. Wang et al. prepared MNs by mixing AIE (aggregation-induced emission)-active polymer PTAC (poly(triphenylamine acrylate)), DOX (doxorubicin), and PTT agent ICG (indocyanine green). Under irradiation, ICG converts light to heat, dispersing polymer particles and releasing DOX, decreasing fluorescence intensity. This process is reversible. After laser off, the polymer particles are reaggregated, as well as the fluorescence intensity is restored [161]. The downside of fluorescence MN sensors is that they require external light excitation, are susceptible to environmental interference, and typically require expensive equipment to detect weak fluorescence signals.

Colorimetric sensing

Colorimetric MN sensors enable in situ visualization of tissue regeneration at injury sites. This method is simple to operate, cost-effective, and results can be observed directly with the naked eye or simple instruments with quantitative RGB analysis. Tetramethylbenzidine (TMB) is commonly incorporated into the tip or backing layer of hydrogel MN, where a cascade reaction between GOx and HRP oxidizes TMB into blue oxidized TMB (oxTMB). By assessing the color intensity of the MN, the glucose concentration in ISF can be determined. For instance, Yin et al. developed a bi-layer MN platform with HRP and TMB added in the backing layer and a PVA/carboxymethyl chitosan (CMCS) hydrogel containing GOx at the tip. This MN sensor enabled visual diabetes detection upon insertion into rat skin for 5 min [162]. Zhao et al. used a similar principle to colorimetrically detect GSH in the body, but they chose the more stable nanozyme Ce-MOF for the oxidase reaction [163]. However, simultaneous colorimetric monitoring of multiple biomarkers is essential, as relying on a single marker often fails to provide an accurate assessment of disease progression or tissue regeneration efficacy. Inspired by colorful tattoos, He et al. added four colorimetric sensing reagents that responsive to pH, uric acid, glucose, and temperature into the HA MN. These MNs featured a patterned and partitioned backing layer, enabling simultaneous monitoring of four biomarkers [164].

Intelligent management of tissue regeneration

Nanosensors refer to sensors that are based on the unique properties of nanomaterials, such as quantum effects, high specific surface area, or exceptional optical/electrical performance, or nanoscale structural designs, to achieve high-sensitivity detection of physical, chemical, or biological signals. As shown in Table 2, integrating them into MNs can not only visualize drug delivery but also monitor tissue regeneration.

Table 2 Applications of nanosensor-MN platforms in tissue regeneration monitoring

For real-time drug monitoring, metal-based NPs such as Au@Ag NPs can enhance the Raman signal of SERS-based MN sensors, which can identify drug molecules through changes in Raman scattering wavelengths [174]. Wang et al. developed a bilayer metal MN patch featuring a Ag/CNT-coated WE and a drug reservoir integrated into the top of the needle tips for wound healing and monitoring. The PET-PTFE-based TENG served as the backing layer, generating electrical stimulation to promote healing. The resulting electric potential repelled negatively charged antibiotics, triggering drug release for antibacterial action. The Ag/CNT MNs functioned as a WE in an electrochemical sensor to monitor wound biomarkers H₂O₂ and uric acid (UA), enabling real-time healing assessment (Fig. 11A) [170]. For monitoring inflammatory factors, antibodies corresponding to the target can be added to the CNT-modified WE [175]. Monitoring wound pH value to guide treatment plans is a widely adopted approach. For example, Xiao et al. added bismuth-porphyrin framework (Bi-PCN-222) loaded with curcumin (Cur) into methacrylated silk fibroin (SilMA) hydrogel to form MN tips, while the backing layer consisted of PVA solution containing fluorescein isothiocyanate (FITC) as the pH-sensitive fluorescent probe [176]. Some nanodrugs with inherent photoluminescence properties can monitor their own residual dose. For instance, Yi et al. developed A-GNCs by modifying chloroauric acid (HAuCl₄) with 4-aminobenzoic acid (ABA) and glutathione (GSH). When delivered into wounds via HA MNs, the UV-triggered color intensity quantitatively reflected the residual drug concentration (Fig. 11B) [171]. SiO₂ NPs, used as template materials in MN, can form inverse opal structures, endowing them with structural color characteristics for sensing pH and histamine [177]. The pores of the inverse opal structure also facilitate drug loading for drug delivery sensing. Lu et al. developed inverse opal-structured MNs using SiO₂ NPs, N-isopropylacrylamide (NIPAM)/PEGDA hydrogel, and BP nanosheets. NIR irradiation triggered drug release through PTT, while the structural color shifts as the hydrogel thermally collapses [178]. This team also modified the tips of the inverse opal-structured MN with LPS aptamer to extract ISF from the skin of infected rats and detect LPS content, thereby assessing the degree of wound infection (Fig. 11C) [179]. For motion monitoring, conductive 2D nanomaterials like MXene are often incorporated into the backing layer of the MN [180]. In summary, the integration of nanosensors and MN technology represents a promising strategy for tissue regeneration monitoring.

Fig. 11

Electrochemical MN sensors, colorimetric MN sensors, and fluorescent MN sensors are used for monitoring tissue regeneration therapy. (A) Integrated TENG electrochemical sensors for monitoring drug release and wound healing [170]. Copyright 2024, Wiley-VCH. (B) Self-luminous nanomedicines with photoluminescence can monitor the remaining amount after being delivered by MNs [171]. Copyright 2024, Wiley-VCH.(C) MNs with inverse opal structures can monitor LPS at the wound site [179]. Copyright 2022, Elsevier

Conclusions and future perspectives

Conclusions

In tissue regeneration therapy, nanomaterials can be functionally categorized into nanotherapeutics and nanosensors. Both can be combined with MN technology to construct nanotherapeutics-MN platforms and nanosensor-MN platforms. Specifically, nanotherapeutics-MN platforms can precisely deliver drugs to promote repair and regeneration in various tissues, while nanosensor-MN platforms can dynamically monitor and provide real-time feedback on critical indicators during regeneration. Furthermore, integrating nanomaterials into a single MN patch can create a closed-loop “treatment-monitoring-regulation” regenerative system, effectively addressing drawbacks of traditional therapies such as excessive repair or delayed response. This synergistic strategy combining nanomedicine and MN technology offers an advanced and promising approach for tissue regeneration therapy, balancing efficiency, precision, and personalization.

For complex and dynamic tissue regeneration needs, the complementary integration of nanomedicine and MN technology offers an advanced strategy. By optimizing MN parameters such as length, geometry and array layout, MN can be precisely matched to different tissues ranging from skin to bone and from superficial to deep layers. In addition, the choice of MN manufacturing materials ensures sufficient mechanical strength for tissue penetration while maximizing biocompatibility. These optimizations enable MNs to cross physiological barriers such as the stratum corneum or cartilage matrix, facilitating deep targeted delivery of nanomaterials. In addition, the modular design and tunable degradation rates allow MNs to dynamically adapt to different tissue repair phases. Such MN optimization can effectively overcome limitations such as imprecise delivery and delayed microenvironmental response encountered when using nanomaterials alone.

Correspondingly, traditional MNs have limited functions that are constrained by limited space. Taking advantage of their small size and versatile properties, multifunctional nanomaterials can be loaded into the confined MN space, enabling efficient integration of antibacterial/anti-inflammatory agents, internal or external stimuli-responsive components (e.g. pH, enzyme, ROS, or UV) and even real-time monitoring units such as electrochemical, fluorescent or colorimetric elements into MNs. Crucially, the combination of MNs with multifunctional nanomaterials is driving the development of wearable micro-devices. Flexible patches integrating MNs and nanomaterials enable precise regulation of multi-level tissue repair and regeneration (from acute inflammation suppression to chronic tissue remodeling) across epidermal to deep layers, while maintaining long-term adhesion for sustained therapy and dynamic monitoring. This synergy creates a platform that can be translated into clinical applications featuring high efficiency, responsiveness, and greater patient compliance.

Challenges and future perspectives

Personalized medicine

The efficacy of tissue regeneration is affected by factors such as the patient’s age, metabolic status, and microenvironment. The current challenge for nanomaterial-MN platforms is to accurately match the biological characteristics of an individual patient in order to achieve personalized regenerative medicine. The therapeutic effects of existing nanotherapeutics show significant individual differences. In the future, by integrating multi-omics data and artificial intelligence (AI) algorithms, we can establish patient-specific biomarker libraries and design customized nanotherapeutics-MN platforms, while combining with real-time biosensor. This approach is expected to enable the MN platform to autonomously regulate drug release according to the patient’s own health or tissue characteristics, thus avoiding generic therapeutic solutions for some individuals that may cause the side effects.

Integration with wearable technology

In tissue regeneration applications, the integration of nanomaterial-integrated MN platforms with wearable technologies offers unique potential for continuous monitoring and real-time feedback. Nanosensor-equipped MN platforms, such as gold nanoparticle-decorated SERS probes or CNT electrochemical sensors, enable real-time detection of critical biomarkers such as glucose, pH, and inflammatory factors in damaged tissues. Current research integrates highly stretchable and electrically stable smart textiles with flexible electronic components into MN platforms to create wearable devices. However, such systems are constrained by heterogeneous material interface stability and multimodal signal crosstalk. For instance, tissue fluid infiltration can induce electrochemical corrosion at nanomaterial-electrode interfaces, leading to signal drift. In the future, the synergistic optimization of interface engineering strategies and intelligent signal processing technologies is expected to overcome these limitations.

Clinical translation and regulatory

The translation of nanomaterial-MN platforms capable of promoting tissue regeneration from the laboratory to the clinic faces many challenges and limitations. This is due to the complex composition of nanomaterials, which increases the difficulty of safety and biocompatibility assessment and requires rigorous long-term toxicological studies in animal models (e.g., mouse or porcine skin models). Additionally, clinical translation must comply with complex regulatory processes such as FDA approval, and the combination of MNs with nanomaterials may introduce additional unknown risks due to synergistic effects, necessitating multi-phase clinical trials for validation. Furthermore, cost control in large-scale production and technical stability (e.g., needle tip strength, uniform drug loading) also limit the speed at which these platforms can be advanced to clinical use. However, with the rapid development of material science, advancements in material design and continuous optimization of automated manufacturing processes are expected to reduce costs. Moreover, in-depth development of organoid technology may accelerate the safety assessment, ultimately facilitating clinical translation.

Global health and accessibility

Despite the promise of nanomaterial-MN platforms for tissue regeneration, their global application is still constrained by practical challenges, including lack of technological maturity, high manufacturing costs and limited evidence of long-term safety. In resource-limited regions and countries, unstable power supply and lack of cold chain infrastructure may affect the performance and drug stability of these platforms. And in the case of self-administration, inadequate training and individual differences can pose a risk of misuse. In the future, the development of low-cost, temperature-stable formulations and the facilitation of localized production through open-source design or simplified manufacturing techniques could progressively increase the global accessibility of the technology. This will help overcome the limitations of traditional healthcare resources and make the nanomaterial-MN platform as a novel tool to enable patients around the world to manage tissue repair autonomously.