TRPV1 Activation via a Three‐Stage Adaptive Heat‐Absorbing Hydrogel Drives Neurovascular–Immune Coupling

Abstract

ABSTRACT Impaired neurovascular–immune coupling severely hampers chronic wound healing. Although the transient receptor potential vanilloid 1 (TRPV1) channel represents a promising therapeutic target, its therapeutic application remains limited by imprecise activation. Here, we developed a three‐stage adaptive and heat‐absorbing hydrogel (termed HMCG) that enables programmable and localized TRPV1 activation under near‐infrared (NIR) irradiation. HMCG forms reversible boronate ester bonds between PVA and TSPBA, enabling a sol–aerosol–gel adaptive with sprayable handling, self‐adaptation, and conformal coverage of complex wound topologies. This dynamic behavior ensures close biointerface contact and controlled thermal regulation during stimulation. Embedded Ca‐gallic acid metal–organic frameworks (MOFs) act as photon‐thermal converters, where ligand‐metal charge transfer and π–π stacking drive rapid nonradiative relaxation, leading to efficient and controllable heat absorption. Brief NIR exposure triggers the sustained release of capsaicin and Ca 2+ , elevating the local temperature to 43°C, within the TRPV1 activation window and with a reduced risk of nonspecific thermal overstimulation. Together, the tri‐stage adaptive design helps buffer heat, maintains topological adaptability, and synchronizes mild photothermal and biochemical cues. This controlled light‐heat‐chemical coupling supports the restoration of neurovascular–immune coupling and promotes tissue regeneration in diabetic skin lesion models, establishing a controlled, programmable platform for TRPV1‐targeted regenerative therapy.