Deep-penetrating tetrahedral framework nucleic acid nanogel spray restores miRNA-223 to potentiate macrophage-driven angiogenesis for deep tissue pressure injuries.

Deep tissue pressure injuries (DTPI) are clinically recalcitrant due to a "dual-barrier" challenge: the dense necrotic tissue that physically impedes drug penetration and the enzymatic microenvironment that accelerates drug degradation. Herein, we identify the spatiotemporal depletion of endogenous microRNA-223 (miR-223) as a molecular driver of chronic inflammation and impaired angiogenesis in DTPI. Hence, we engineered an in situ self-solidifying nanogel spray (TRF) by encapsulating sticky-end miR-223-loaded deep-penetrating tetrahedral framework nanodevices (T-223) within a thermosensitive matrix. Specifically designed to tackle the dual barriers, the T-223 cage shields the miRNA cargo from nuclease degradation while leveraging its tetrahedral geometry to penetrate the necrotic tissue, thereby replenishing the depleted miR-223 pool in deep-seated lesions. Mechanistically, T-223 reprograms the inflammatory microenvironment by repolarizing macrophages toward a pro-regenerative M2 phenotype, which subsequently directs endothelial cell migration and proliferation to restore the macrophage-mediated immune-vascular axis. The in situ gelation of the TRF spray ensures conformal coverage of irregular wound cavities, preventing drug washout. In a murine DTPI model, the "nutrient reservoir" TRF releases the "molecular fertilizer" T-223 to debride the deep necrotic "soil," accelerating healing and achieving functional repair characterized by synergistic anti-inflammation and pro-angiogenesis. This study establishes a non-invasive and deep-penetrating "molecular debridement" strategy, offering a therapeutic solution for similar chronic wounds.