Chronic diabetic wounds present substantial clinical challenges owing to sustained inflammation, compromised vascularization, and inadequate retention of therapeutic medications. Accordingly, motivated by mesenchymal stem cells (MSCs) that actively secrete bioactive exosomes in response to stimuli from the tissue microenvironment, a biomimetic microneedle (MN) platform (MSCi@MN) is created to address these challenges. The MSCi@MN exhibits a dual-compartment structure composed of MSC-derived extracellular nanovesicles (NV) conjugated with polydeoxyribonucleotide (PDRN; DNA), referred to as NV-DNA, encapsulated within dissolvable MN tips, and photothermal-responsive MXene nanoparticles (MX) incorporated into the base layer for targeted near-infrared (NIR)-activated drug delivery. Upon NIR irradiation, MSCi@MN quickly releases NV-DNA, effectively modifying the immune responses by facilitating anti-inflammatory M2 macrophage polarization and activating tolerogenic dendritic cells, thereby establishing a regenerative microenvironment. Transcriptomic research has verified that NV-DNA synergistically promotes angiogenesis, cellular proliferation, and extracellular matrix remodeling by activating complementary molecular pathways. In animal models of diabetes, MSCi@MNs markedly expedite wound repair, diminish inflammation, enhance angiogenesis, and restore skin appendages without systemic adverse effects. This MSC-inspired approach, which integrates biologically sensitive controlled release with robust immunoregenerative capabilities, has substantial potential for clinical use in chronic wound treatment and regenerative medicine.
