The Synergistic Applications of Microneedling and Nanomaterials: Attaining Cutaneous Repair

Microneedle length

The structural thickness of human skin varies across different anatomical sites. This analysis primarily references the characteristic layered thickness of the inner forearm for discussion. To achieve effective drug delivery, microneedles must penetrate the epidermal layer (>0.1 mm) and reach the vascular-rich dermal layer (<2 mm).^20,21 Consequently, microneedle lengths are predominantly designed within the 0.1–2 mm range. ²² The clinical implications associated with different microneedle lengths are summarized as follows: (1) 0.1–0.3 mm: enables epidermal penetration, enhancing the transdermal permeation efficiency of active ingredients ²³ ; (2) 0.3–0.8 mm: accesses the papillary dermis, leveraging its high-density immune microenvironment (e.g., Langerhans cell clusters) to potentiate vaccine efficacy. For example, glioblastoma vaccines can utilize this mechanism to elicit specific CD8⁺ T cell responses ²⁴ ; (3) 0.8–1.5 mm: reaches the reticular dermis, where the dense vascular and lymphatic networks facilitate enhanced delivery efficiency for macromolecular drugs such as insulin ²⁵ ; and (4) 1.5–2.0 mm: while this depth contains high neural density that may induce pain, studies indicate its potential for modulating hair follicle activity in alopecia treatment. ²⁶

Diameters and array density

Diameter balances penetration mechanics and neural sensitivity ²¹ : smaller diameters reduce the likelihood of stimulating nerve endings (decreasing pain) but risk structural bending; larger diameters improve stability and drug-loading capacity, but it requires greater insertion force and intensifies pain due to increased contact with neural tissue and amplified tissue trauma. ²⁷ Array density impacts delivery: high density increases release rates and prevents occlusion via multichannel effects, but excessively high density can lead to the “nail bed effect,” where the skin is uniformly pushed down without being penetrated.^27,28 Optimal design integrates both parameters: high-density/small-diameter arrays minimize discomfort in sensitive areas, while low-density/large-diameter configurations are suited for applications that demand the delivery of high-dose drugs or need to penetrate challenging, thicker cutaneous layers.

The topological structure of needles

Current microneedle tip configurations predominantly include conical and beveled geometries. To optimize penetration capability and tissue adhesion, researchers have developed specialized tip architectures.

Penetration optimization: Serrated tips, inspired by mosquito proboscis, reduce insertion force via vibrational motion during application, improving penetration with less discomfort. ²⁹

Adhesion enhancement: Strategies focus on increasing microneedle–tissue friction to prevent shedding: (1) Swellable structures: hydrogels rapidly absorb interstitial fluid (e.g., CH-Arg/PVA hydrogel exhibiting 800 ± 50% swelling in phosphate-buffered saline ³⁰ ), expanding intradermally to enhance mechanical anchorage. ³¹ (2) Bioinspired structures: designs mimicking natural systems (e.g., shark tooth barbs, ³² porcupine quill, ³³ goosegrass microhooks ³⁴ ) mechanically interlock with tissue via barbs to prevent displacement. ³⁵ (3) Hybrid adhesion: combining vacuum-assisted suction and chemical bonding yields superior adhesion. For instance, a mussel-octopus bionic system integrates a polydopamine (PDA) hydrogel base (catechol-mediated chemical adhesion) with octopus-sucker-inspired conical tips featuring concave cavities for vacuum sealing. This provides robust adhesion in both dry and moist conditions (Fig. 2). ³⁶ Needle topology is fundamental to penetration, drug delivery, and fluid extraction efficacy. Fabrication advances enable precise tailoring of these geometries for specific applications.^21,27

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FIG. 2.

Biomimetic structure schematic diagram.^32–34,36 (A) Scanning electron microscope (SEM) images of the polyurethane (PU) microneedles under low and high magnification. (B) SEM images of the PU microneedles under low and high magnification with a tilt angle of 20°. Adapted with permission from Ref. ³⁴ . Copyright 2025 Wiley. (C) Fabrication and characterization of the bioinspired multifunctional microneedles. Adapted with permission from Ref. ³⁶ . Copyright 2025 Science Partner Journals. (D) Micrograph of shark tooth-inspired needles. (E) SEM images of shark tooth-inspired needles. (F) Optical images of microneedles in a snow pattern. (G) Optical images of stretched microneedles. Adapted with permission from Ref. ³² . Copyright 2025 American Chemical Society. (H) Analysis of porcupine spurs. Adapted with permission from Ref. ³³ . Copyright 2025 Proceedings of the National Academy of Sciences (PNAS).

In addition, needle physical structure, needle body angle, thickness, coating thickness, and the design of the base substrate all significantly impact performance.

Solid microneedles

Solid microneedles, fabricated from metals, silicon, or polymers, lack intrinsic drug-carrying capacity or delivery channels. Their mechanism of action involves creating microchannels through skin/biofilm/granulation tissue penetration, followed by passive drug diffusion via transdermal patch application.^66,67 Metallic microneedles provide superior mechanical strength for deep tissue access, while degradation products (e.g., magnesium microneedles release Mg²⁺ and H₂ during biodegradation, thereby regulating keratinocytes and exerting anti-inflammatory effects) enable synergistic therapy.^38,40 These devices exhibit biocompatibility, supporting clinical safety and reusability.^37,68 However, limitations include noble metal costs impeding mass production, ⁷ therapeutic dependence on secondary patches restricting standalone use, and risks of retained microtips triggering foreign body reactions that impair healing. ⁶⁹

Coated microneedles

Coated microneedles feature a shaft surface coated with drug molecules, enabling barrier penetration for targeted drug delivery. This design increases local drug concentration, improving therapeutic efficacy, bioavailability, and controlled release. ⁷⁰ Coated microneedle fabrication uses methods such as dip-coating and casting. ⁷¹ They are also suitable for in vivo sampling, as demonstrated by an alginate-peptide nucleic acid hybrid hydrogel coating that selectively captures specific miRNA through base complementation for detection. ⁷² Metallic-coated microneedles maintain structural integrity due to material stability, allowing repeated drug delivery.^37,68 Silicon-based systems combine nanowire arrays with silver-catalyzed etching techniques to increase drug-loading capacity while maintaining puncture resistance. ⁴³ Key limitation: restricted drug-loading capacity impedes high-dose applications, necessitating improved coating technologies for enhanced delivery efficiency and biomedical utility.

Dissolving microneedles

Dissolving microneedles are made of biodegradable materials. After insertion into the skin, they dissolve gradually, releasing encapsulated therapeutic agents. ⁵⁹ This characteristic makes them an ideal platform for encapsulating nanocarriers, thereby enabling the precise delivery of nanotherapeutic agents to deep wound regions for targeted treatment. These microneedles require biocompatible materials to avoid toxicity from dissolved substances.^8,52,59,73 Besides drug delivery, their degradation products can promote tissue regeneration by stimulating cell migration, angiogenesis, and collagen synthesis. ⁷⁴ For example, hyaluronic acid (HA)-based systems modulate macrophage polarization (M1-to-M2 switching) to suppress inflammation while promoting CD44 receptor-mediated endothelial migration for vascularization, enhancing HA-assisted wound healing. ⁸ After dissolving, they restore tissue integrity and prevent additional damage from extraction.

Hollow microneedles

Hollow microneedles contain internal channels that allow drug injection under external pressure from a pump or syringe. They can be made of metals, silicon, or polymers. Hollow microneedles can deliver multiple drugs without repeated insertions, ⁷⁵ with controllable drug release parameters including type, dose, and flow rate. These microneedles can incorporate internal electrodes to detect body substance concentrations. ³⁷ Using silicon’s semiconducting properties, researchers have integrated microelectro-mechanical system ⁴³ and biosensing modules ⁷⁶ in microneedle lumens to detect interstitial fluid biomarkers for minimally invasive diagnostics. However, the internal channels may become blocked by cutaneous tissue, hindering drug injection. ²⁷

Stimuli-responsive microneedles

Stimuli-responsive microneedles consist of hydrophilic hydrogels that absorb water and expand upon insertion into the body, interacting with surrounding tissues and anchoring the microneedles through the mechanism of the previously mentioned swellable structures. ³¹ The hydrogel absorption removes excess exudates from wounds. ⁷⁷ By responding to pH and temperature changes, they control drug release and improve targeting. ⁵² Stimuli-responsive microneedles have greater drug-loading capacity than other types while delivering various therapeutic agents like growth factors, cells, and DNA. They are also easy to fabricate and cause little wound irritation, ⁷⁸ making them promising for drug delivery and wound management.

This taxonomic system provides a framework for clinical compatibility screening of microneedle systems. However, current classification standards have three main limitations: (1) existing classification methods (by material composition, structure, and drug release mechanisms) lack a unified framework; (2) new microneedle technologies challenge traditional classification approaches; and (3) most importantly, there is no classification system guided by clinical translation principles.

Metal and metal oxide nanomaterials

Drug loading strategies for metal/metal oxide nanomaterials primarily encompass the following: covalent conjugation (e.g., Au–S bonds in gold nanoparticles ⁷⁹ ) ensures payload stability but risks conformational changes; physical adsorption (e.g., polyethylenimine-modified silver carriers ⁸⁰ ) offers simplicity with limited efficiency; mesoporous encapsulation (e.g., Fe₃O₄@SiO₂ ⁸¹ ) enhances drug capacity but requires burst release control.

These nanomaterials exert bactericidal effects via membrane disruption, enzyme inhibition, and reactive oxygen species (ROS) generation. ⁸² For example, silver nanoparticles release Ag⁺ ions that bind with sulfhydryl (–SH) groups in bacterial membranes, disrupting the electron transport chain and inhibiting nicotinamide adenine dinucleotide hydride dehydrogenase activity. The tannic acid-synthesized silver nanoparticles inhibit methicillin-resistant staphylococcus aureus (MRSA) and other resistant strains, ⁸³ and silk fibroin microspheres (SFM)-AgNPs composite shows broad-spectrum antibacterial activity. ⁸⁴ The Au-Cu₂MoS₄ (Au-Cu2MoS4 的缩写 [CMS]) nanoplatforms combine enzymatic glucose oxidase/catalase activity with photothermal effects.^40,85

In tissue regeneration, copper nanomaterials activate MEK1/PDK1/PI3K proliferation pathways while promoting angiogenesis via NF-κB/HIF-1α regulation. ⁸⁶ For anti-inflammatory applications, MnO₂ nanoparticles convert excess ROS to oxygen via catalase/superoxide dismutase-mimetic (CAT/SOD) activity. ⁷⁷ MgO nanoparticles release Mg²⁺ to induce M2 macrophage polarization, enhancing tissue repair and vascular formation to mitigate inflammation. ⁸⁷

Metal-organic frameworks

Metal-organic frameworks (MOFs) are crystalline porous materials formed by metal ion-organic ligand self-assembly. For cutaneous repair drug delivery, MOFs must meet specific structural requirements: pore sizes 1.5–2 times larger than therapeutic molecules, ⁸⁸ active group functionalization (e.g., amino/carboxyl) enhancing drug adsorption, ⁸⁹ topological design improving hydrothermal stability and mechanical strength, ⁹⁰ and stimuli-responsive (e.g., pH/light) properties enabling controlled release. ⁹¹ Common dermal MOFs include zinc-based ZIF-8 (Zn²⁺/2-methylimidazole), ⁵¹ iron-based MIL-101 (Fe³⁺/1,4-benzenedicarboxylic acid), ⁵⁹ zirconium PCN-224 (Zr⁶⁺/5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin), ⁹² magnesium Mg-MOF-74 (Mg²⁺/2,5-dihydroxyterephthalic acid), ⁹³ and hybrid Zn-MOF-hydrogel systems. ⁹⁴

These materials exert antimicrobial effects through metal nodes (Cu²⁺/Ag⁺/Zn²⁺) and ligands (imidazole/porphyrins), disrupting biofilms via charge-modulated hydrophobicity,^51,95 with ZIF-8 exemplifying multimechanism action via membrane damage, glutathione (GSH) depletion, ROS induction, and anti-inflammatory cytokine upregulation.^54,96 MOFs also exhibit anti-inflammatory, proangiogenic, and tissue-regenerative properties. The gallic acid/Cu-based MOF (CuGA-MOF) system releases Cu²⁺ to prolong therapeutic time while reducing cytotoxicity. Cu²⁺ drives neovascularization via HIF-1α/vascular endothelial growth factor (VEGF) signaling. ⁹⁷

Silicon nanomaterials

Silicon nanomaterials provide high drug-loading capacity, surface modifiability, and biocompatibility. Mesoporous silica nanoparticles (MSNs) incorporating betamethasone dipropionate offer a new psoriasis treatment strategy. MSNs regulate drug adsorption/release and provide targeting, enhancing local drug efficiency. ⁵⁷ Intracellular degradation of MSNs releases Si²⁺ ions that activate HIF-1α/VEGF signaling to drive angiogenesis via endothelial progenitor cell recruitment. ⁹⁸ Thiol-functionalized MSNs modulate NF-κB-mediated inflammation through surface sulfhydryl groups.^99,100 For diabetic wounds, silicon nanoparticles coloaded with glucose oxidase and metformin reduce local glucose while generating antibacterial ROS, promoting wound healing. ¹⁰¹

Polymer nanomaterials

Polymer nanomaterials provide biocompatibility, diverse fabrication methods, and controlled drug delivery. Some exhibit biological activity: chitosan nanomaterials use cationic surfaces to enhance cell migration through electrostatic membrane interactions ¹⁰² and show broad-spectrum antibacterial activity. ¹⁰³ PDA nanomaterials reduce inflammation by scavenging radicals and inhibiting NF-κB signaling and NLRP3 inflammasome assembly. ¹⁰⁴ These materials encapsulate antibacterial agents for microneedle delivery into biofilms, releasing agents upon nanoparticle dissolution.

Exosomes

Exosomes are cell-derived nanovesicles with biocompatibility, targeting precision, and modifiability. ¹⁰⁵ In wound repair, the core function of exosomes is to regulate inflammatory pathways and drive vascular regeneration. Platelet-derived exosomes (PLT-Exos) reduce inflammation via NF-κB inhibition and macrophage polarization, while promoting angiogenesis through VEGF/fibroblast growth factor activation. ¹⁰⁶ Mesenchymal stem cell exosomes activate fibroblasts, endothelial cells, and macrophages to drive vascular remodeling and immune balance. ¹⁰⁷ Human mesenchymal stem cell exosomes polarize macrophages to M2 by suppressing NF-κB and upregulate VEGF/HIF-1α to enhance regeneration.^108,109 Rejuvenated fibroblast exosomes (Y-EXO) improve aged cutaneous repair by accelerating healing, increasing collagen, and reducing IL-17A. ¹¹⁰ During wound repair processes, M2 macrophage exosomes promote angiogenesis via Wnt/β-catenin signaling in granulation tissue, optimizing the regenerative microenvironment. ¹¹¹

Liposomes

Liposomes are phospholipid vesicles that encapsulate DNA, proteins, and small molecules for controlled drug delivery. ⁶⁰ Functionalized liposomes loaded with NACHT, Leucine-Rich repeat, and pyrin Domains-Containing Protein 3 (NLRP3) inhibitor MCC950 reduce inflammation by polarizing macrophages from M1 to M2 and enhancing fibroblast–endothelial communication, improving tissue regeneration. ¹¹² A macrophage-derived liposome system delivers purpurolide C (PC), which inhibits NF-κB phosphorylation to regulate macrophage function. This system enhances PC bioavailability and accelerates diabetic wound healing through polarization reprogramming. ¹¹³

Through a systematic review of the aforementioned content, it can be observed that inorganic nanomaterials confer antibacterial and enzyme-mimetic catalytic functions through their physicochemical properties, enhancing wound therapy efficacy. Organic nanomaterials provide biocompatibility and targeting capabilities for precision treatment. Integration with microneedle platforms enables precise regulation of wound healing processes. However, clinical application faces challenges: inorganic nanomaterials need long-term biosafety evaluation, while organic nanomaterials face immunogenicity risks and stability issues. To provide a clearer overview of current research progress, Table 2 systematically summarizes the performance characteristics and limitations of commonly used nanomaterials in microneedle technology.

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Table 2.

Advantages and Disadvantages of Nanomaterials Combined with Microneedles

	Nanomaterials
	Inorganic nanomaterials			Organic nanomaterials
	Metal and metal oxide nanomaterials	Metal-organic frameworks (MOF)	Silicon nanomaterials	Polymer nanomaterials	Exosomes	Liposomes
Advantages	Antibacterial efficacy, 83 nanozyme catalysis, 40 promote tissue regeneration and proangiogenic effect, 86 inflammation suppression 77	High payload capacity, 91 stimuli-responsive release, 91 multifunctional integrated platform, 89 antibacterial efficacy, 51 promote tissue regeneration and proangiogenic effect, 57 inflammation suppression 57	High payload capacity, 98 surface engineering capacity, 98 excellent biocompatibility, 102 proangiogenic effect, 100 inflammation suppression 101	Antibacterial efficacy, 104 excellent biocompatibility, 16 versatile fabrication strategies, 102 promote tissue regeneration and proangiogenic effect, 103 inflammation suppression 105	Promote tissue regeneration and proangiogenic effect,107,108 excellent biocompatibility, 60 targeting capability, 106 engineering versatility, 106 inherent barrier-penetrating capacity 106	Excellent biocompatibility, 112 targeting capability, 112 inherent barrier-penetrating capacity, 112 inflammation suppression 113
Disadvantages	Cytotoxicity, 114 Immunogenicity, 115 Long-term accumulation risks, 116 Aggregation tendency and rapid clearance 117	Cytotoxicity, 118 low stability, 88 high scale-up production costs 119	Uncontrolled degradation rate, 120 aggregation tendency 121	Immunogenicity, 122 long-term accumulation risks, 123 low stability 124	Storage challenges, 125 low production yield, 126 poorly understood mechanisms 38	Low payload capacity, 127 high production costs, 128 low encapsulation efficiency, 128 low stability 129

Inhibition of fibroblast proliferation

Suppressing aberrant fibroblast proliferation is key to reducing pathological thickness in HS. Studies show that miR-141-3p inhibits HS fibroblast proliferation but is downregulated in pathological microenvironments. To overcome this, researchers developed a microneedle exosome delivery system that precisely transports miR-141-3p-overexpressing exosomes (miR-141-3p-OE-Exos), inhibiting fibroblast proliferation in HS models (Fig. 4A). Histological analysis demonstrated a significant reduction in scar thickness and restoration of organized fibroblast architecture in the experimental group compared with controls (Fig. 4A), confirming that microneedle-delivered exosomes effectively inhibit HS formation. ⁸

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FIG. 4.

(A) Effect of miR-141 OE-Exos on morphological changes in HS. ⁸ Copyright 2025 Wiley. (B) Hematoxylin and Eosin (H&E), Masson trichrome, and CK14/CK19 (hair follicle/sebaceous gland markers) immunofluorescence staining of cutaneous tissue at day 90. ⁵² Copyright 2025 Elsevier. (C) Ultrasound images of the scars after 3 weeks of microneedle intervention. (D) Statistical analysis of thickness of scars by ultrasound examination. ⁵¹ Copyright 2025 Wiley. (E) Immunofluorescence staining of CD31. (F) Quantification of capillary density in different groups (n = 6). (G) Immunofluorescence staining of IL-6. (H) Immunofluorescence staining of TNF-α. ⁸⁷ Copyright 2025 ACS. HS, hypertrophic scars.

Building on synergistic therapeutic principles, a bismuth nanosheet-verteporfin (Vp) composite microneedle penetrates scar tissue/biofilms for dual-action therapy. Bismuth exerts broad-spectrum antibacterial effects, while Vp inhibits the yes-associated protein (YAP) pathway to block fibroblast hyperproliferation. Longitudinal monitoring confirmed complete prevention of pathological scarring within 90 days, with tissue progressively normalizing to native morphology (Fig. 4B). ⁵²

Ferroptosis

Ferroptosis plays a pivotal role in the treatment of HS. Pathological analysis reveals iron metabolism dysregulation in HS myofibroblasts, which activates the ferroptosis process. To promote this therapeutic mechanism, Dr. Bin Zhao’s team constructed an AgNC/TRG/ZIF-8 composite by coloading silver nanoclusters (AgNC) and trigonelline (TRG) into ZIF-8 frameworks, delivered via microneedles. This system promotes myofibroblast ferroptosis: ZIF-8/AgNC reduced GSH by 50% versus controls, while TRG suppressed GPX4 activity and NRF2 pathway—key ferroptosis regulators. α-smooth muscle actin (α-SMA) and collagen I/III were downregulated in HS tissues. Microneedle delivery reduced HS thickness from 3.5 ± 0.3 mm to 1.8 ± 0.1 mm after 3 weeks (Fig. 4C, D). ⁵¹

Remodeling the pathological microenvironment of HS

Remodeling the pathological microenvironment of HS is a crucial strategy for reducing abnormal scar formation. Studies have demonstrated that the precise delivery of 5-fluorouracil (5-Fu) via a microneedle system, when encapsulated in sodium carboxymethyl cellulose nanoparticles, plays a significant role. As a pyrimidine analogue with antimetabolic activity, 5-Fu effectively inhibits fibroblast proliferation and suppresses abnormal angiogenesis by regulating the Bcl-2-associated death promoter, insulin-like growth factor 1 receptor (IGF1R) pathway, remodeling the pathological microenvironment of HS, and promoting normal wound healing. ¹³² Microneedle-delivered nanomaterials increase neovascular density to 57.2 ± 2.3/mm², reduce IL-6/TNF-α to 29.84 ± 2.46% of controls, alleviate microcirculatory dysfunction, and create a prohealing immune microenvironment (Fig. 4E–H). ¹⁰¹

Photodynamic therapy

Photodynamic therapy (PDT) generates antibacterial ROS via photosensitizer activation at specific wavelengths. ⁵³ A Dimethyloxalylglycine (DMOG) @PCN-224 MOF coloaded with meropenem (MEM) in HA microneedles releases nanoparticles upon delivery. Under 650 nm laser, nanoparticles convert O₂ to ¹O₂/OH, synergizing with MEM to achieve equivalent sterilization at lower antibiotic doses than monotherapy (Fig. 6A–C). Furthermore, DMOG activates HIF-1α to stimulate neovascularization, combining with PDT for 96.4 ± 0.7% wound closure by day 11 (Fig. 6D). ⁹² For sustained antimicrobial effects, Cu²⁺-doped Zn₂GeO₄ long-afterglow nano catalysts (ZGC), preactivated by laser, continuously produce ROS via cascade reactions (Fig. 6C). Experimental results demonstrated a significant reduction in MRSA viability under prolonged illumination (Fig. 6E–I). ¹³⁶

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FIG. 6.

Representative photographic images of inhibition zones against (A) Escherichia coli, (B) Staphylococcus aureus, and (C) Pseudomonas aeruginosa with different treatments. Black dashed squares indicate the application position of MN patch, and red dashed circles indicate the inhibition zone. (D) Schematic diagram of wound morphological changes in different groups within 11 days. ⁹³ Copyright 2025 Wiley. (E, F) Photographs of MRSA colonies formed on LB agar plates and the (G) relative bacterial survival rate of MRSA after incubation with various concentrations of ZGC with and without preillumination. Data were presented as the mean ± SD (n = 3). (H) Live/dead fluorescent bacterial staining and (I) SEM images of MRSA treated with 0 and 1 mg mL − 1 ZGC dispersion with preillumination. ¹³⁵ Copyright 2025 ACS. MN, microneedle; SD, standard deviation.

Photothermal therapy

Photothermal therapy (PTT) uses photosensitizers to convert specific-wavelength light into heat, eliminating bacteria through hyperthermia while avoiding antibiotic resistance. ⁵² MnO₂ NPs and PDA materials show photothermal antibacterial effects under near-infrared radiation (NIR) light.^77,101 Lei Xiaoling’s team encapsulated antimicrobial peptide (AMP)-Cypate in gelatin nanoparticles (GNPs) for microneedle delivery, combining peptide activity with photothermal effects. At 6 μg/mL, this system achieves >90% killing of Staphylococcus aureus, with MIC₉₀ reduced from 6 to ∼4 μg/mL under NIR (Fig. 7A). ¹³⁵ Furthermore, PTT-generated heat can propel nanoparticles, as demonstrated by a microneedle-delivered nanomotor system (PMV nanogel/indocyanine green (ICG)/L-Arg). NIR-activated ICG provides direct antibacterial effects and drives nanomotor penetration; concurrently, heat-triggered NO release from L-Arg inhibits bacterial proliferation by disrupting DNA repair. Animal studies confirmed a 90% wound healing rate after 7 days with NIR treatment, supported by histological evidence of reduced granulation tissue gaps (Fig. 7B–E). ¹³⁹

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FIG. 7.

(A) Representative fluorescence images for the live/dead staining assay of Staphylococcus aureus incubated with AMP-Cypate@GNPs before and after NIR laser irradiation. ¹³⁷ Copyright 2025 Elsevier. (B) Schematic diagram of the preparation process of nanomotors-loaded microneedle patches and the mechanism of microneedle patches used in wound antibiofilm therapy. (C) Representative photos of the cutaneous wounds of different groups on days 0, 4, and 8. (D) The wound healing efficiency of different groups. (E) H&E staining (upper row) and Masson staining (lower row) of wounds in different groups after treatment. ¹³⁸ Copyright 2025 Elsevier.

Ultrasonic response

Ultrasound-responsive materials absorb, reflect, scatter, and propagate sound waves. Ultrasound penetrates skin and connective tissues beyond 5 cm depth. Based on this, Xiang Yiming’s team developed zinc tetracarboxyphenyl porphyrin (ZnTCPP) @ZnO MOF/ZnO composites delivered by microneedles. Under ultrasound, this system generates ROS for sterilization while enhancing catalytic efficiency and reducing energy consumption. Against Propionibacterium acnes, ultrasound-activated treatment achieved 99.73% antibacterial efficacy (Fig. 8A–C). ⁹⁵ TiO₂ is a classical sonosensitizer, producing ultrasound-triggered ROS with high stability and biocompatibility. ¹³⁷ Recent CuO₂/TiO₂ heterostructures—combining ultrasmall CuO₂ nanoclusters and oxygen-deficient OV-TiO₂ nanosheets—enable synergistic CDT/sonodynamic therapy. This eradicated 82% of MRSA and 81% of Pseudomonas aeruginosa biofilms, with >7-log reduction (>99.99% inhibition) in bacterial colonies (Fig. 8D–N). ¹³⁸

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FIG. 8.

(A) Number of P. acne colonies after treatments with different samples. (B) SEM images of P. acne colonies after treatments with different samples. (C) Protein leakage concentration for P. acne. ⁹⁶ Copyright 2025 Science Advances. (D) Photographs of colonies of MRSA and Pseudomonas aeruginosa treated with CuO₂/TiO₂, TiO₂, CuO₂, or control in the presence and absence of ultrasound. (E, F) Bacterial viability of (E) MRSA and (F) P. aeruginosa upon different treatments. (G, H) Comparison of antibacterial activity with most reported sonosensitive materials at different (G) concentrations and (H) sterilization conditions. (I, J) Crystal violet staining images of (I) MRSA and (J) P. aeruginosa biofilms upon different treatments. (K, L) Relative biofilm biomass for (K) MRSA and (L) P. aeruginosa upon different treatments. (M, N) Resistance development during the passaging treatment with MIC50 of CuO₂/TiO₂, (M) penicillin for MRSA, and (N) gentamicin for P. aeruginosa. ¹⁴⁰ Copyright 2025 Elsevier.

Enzymes

Hypoglycemic therapy corrects dysregulated glucose metabolism in diabetic wounds, improving immune function and enhancing autologous immune cell antibacterial capacity. Enzymes such as GOx effectively lower blood glucose. Loading GOx into MOFs protects it from degradation before reaching wounds, increasing utilization efficiency.^54,59 Traditional agents (e.g., metformin and insulin) delivered via microneedles also achieve glycemic control. ¹⁴¹ The enzyme cascade strategy enhances antibacterial efficacy. Researchers constructed a microneedle system coloading α-amylase and GOx into MIL-101: α-amylase degrades bacterial EPS to disrupt biofilms while generating glucose; GOx utilizes wound glucose (including EPS products) to produce H₂O₂; MIL-101 catalyzes H₂O₂ conversion into ROS for sterilization. This achieves 90% antibacterial efficiency (Fig. 9A). ⁵⁹ Further work developed a biofuel cell–microneedle system coencapsulating GOx/horseradish peroxidase in ZIF-8, controlling glucose through metabolism while generating anti-inflammatory microcurrents. It achieves complete wound healing by day 21, outperforming controls (Fig. 9B). ⁵⁴

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FIG. 9.

(A) Glucose content of biofilms treated with different concentrations of α-amylase. (B) Residual biomass of biofilms after different treatments. (C) Statistical results of biofilm thickness from CLSM image. (D) Photographs of MRSA colonies on LB medium isolated from biofilms. (E) Digital photographs of MRSA colonies after being treated by different MNs. (F) Animal wound healing by different MNs on days 0, 7, 14, and 21. ⁵⁹ Copyright 2025 Elsevier. (G) Quantitative analysis of the wound area after treatment with different samples. (H) Representative images of the H&E staining (n = 3 per group; blue arrows, hair follicles; orange arrows, gland structure). ⁹⁷ Copyright 2025 Science Advances. MN, microneedle.

The microneedle–nanomaterial system addresses three core wound management challenges: (1) precise fibroblast modulation enabling restorative healing with minimal scarring, (2) inflammatory response regulation, and (3) multidimensional antimicrobial protection. These capabilities establish it as a versatile platform for comprehensive wound healing. However, clinical translation faces three obstacles: first, most studies rely on standardized animal models (e.g., murine full-thickness defects) that poorly replicate human chronic wound complexity; second, synergistic therapeutic interactions are poorly understood with inadequate combinatorial toxicity assessment; and third, unified efficacy evaluation standards are lacking.