A template-defined TA-Fe nanoplatform enables mechanistic decoupling and lysosome-gated immunomodulation for diabetic wound healing.

Complex injury microenvironments often render conventional extracellular delivery a "black box", where efficacy is constrained by the efficiency-off-target trade-off, signal distortion by inflammation/ROS, and limited causal attribution of the mechanism. Here, using TA-Fe@PS as a representative material system, we explore lysosome-associated intracellular activation as a strategy to improve immunomodulatory nanotherapy by leveraging macrophage uptake and lysosomal acidity. As a representative material system, we develop TA-Fe@PS, an immunomodulatory nanoplatform constructed by template-directed synthesis on polystyrene (PS) microspheres. In this design, the PS core provides a size-defined interfacial scaffold for uniform TA adsorption and localized Fe3+ coordination, thereby improving particle uniformity, colloidal stability, and dispersion reproducibility compared with template-free TA-Fe assemblies. Mechanistically, macrophage internalization routes TA-Fe@PS into lysosomes, where acidic conditions destabilize the metal-phenolic network and trigger a concerted intracellular release of TA and Fe3+. This lysosome-associated activation attenuates oxidative stress, reduces NF-κB-associated inflammatory signaling, and promotes STAT3-associated reparative programs, thereby guiding macrophages toward an M2-like, pro-reparative phenotype. Transcriptomic profiling supports broad induction of reparative pathways, including Arg-1, IL-17-related signaling, and extracellular matrix remodeling linked to collagen biosynthesis and angiogenesis. In a diabetic full-thickness wound model, TA-Fe@PS accelerates wound closure and improves repair quality, including re-epithelialization, organized collagen deposition, neovascularization, and sustained M2 polarization, without detectable systemic toxicity. Importantly, the PS-templated architecture provides a more defined material platform, allowing the contribution of the coordinated TA-Fe nanostructure to be interpreted more clearly in comparison with template-free Fe-TA assemblies and freely available Fe3+ controls. Together, these results present a template-defined TA-Fe nanoplatform with lysosome-associated immunomodulatory activity for chronic inflammatory wound repair.