Spatiotemporal Immunomodulation of Macrophages via NLRP3/IL‐1β Pathway by Core‐Shell Microneedles to Promote Healing of Biofilm‐Infected Diabetic Ulcers

Abstract Macrophage phenotypic dysregulation, spatially by biofilm and dynamically in time, impedes the healing of diabetic ulcers (DUs). Effective treatment requires enabling spatiotemporal regulation of macrophage polarization, balancing the M1 pro‐inflammatory antimicrobial response with the M2 anti‐inflammatory tissue‐regeneration response. Here, a core‐shell microneedle system (LM‐MG@MN) is proposed with spatiotemporal immunomodulation features, designed to spatially disrupt biofilm barriers and sequentially induce macrophage polarization from M0 to M1 and subsequently to M2 by regulating the NLRP3/IL‐1β pathway. Glucose oxidase (GOX)‐loaded 2D MXene nanosheets (MG) are encapsulated in a hyaluronic acid‐β‐cyclodextrin (HA‐β‐CD) matrix as the MN shell layer. The rapid dissolution of this shell triggers MG to induce pro‐inflammatory polarization of macrophages from M0 to M1, aiding in clearing biofilm infections. Liposomes (LM) carrying the NLRP3 inflammasome inhibitor MCC950 are embedded within a methacrylate hyaluronic acid (HAMA) matrix in the MN core. In the later stages of wound healing, LM is released gradually from the core, promoting the anti‐inflammatory polarization of macrophages from M1 to M2 and accelerating tissue regeneration by enhancing crosstalk with fibroblasts and endothelial cells. Additionally, RNA sequencing indicates that LM‐MG@MN regulates macrophage metabolic reprogramming to enhance DUs healing. This spatiotemporal immunomodulation strategy offers a promising approach for clinical DUs treatment.