Covalently Self-Polymerized Bioactive Poly(dopamine-silicon) Nanoplatform Reprograms Macrophage Metabolism, Modulates Redox Homeostasis, and Promotes Efficient Angiogenesis for Inflammation Injury Repair.

Abstract

The inflammation-related tissue injury repair is still a challenge, in which the metabolic disturbance of macrophages induces cascade amplification of inflammatory mediators and hinders tissue repair. Herein, we developed covalently self-assembled poly(dopamine-silicon) nanoparticles (DS NPs) that integrate enzyme-mimetic catalysis with bioactive ion release to achieve sequential redox modulation and metabolic immune regulation in infected wounds and lung injury models. The covalent linkage reorganized dopamine into a stable amorphous network, preventing π-π stacking and exposing reactive catechol groups, thereby enhancing antioxidant and superoxide dismutase-like activities, which efficiently eliminated reactive oxygen/nitrogen species and corrected oxidative imbalance. Meanwhile, DS NPs supported mitochondrial oxidative phosphorylation and modulated macrophage polarization toward an M2 phenotype with an 89% reduction in TNF-α expression. The immunometabolic reprogramming promoted the transition from inflammation to regeneration, while the sustained release of bioactive silicate ions synergistically promoted angiogenesis by upregulating ANG expression in HUVECs by 2.06-fold. As a proof of concept, in MRSA-infected wound and the early inflammatory stage of acute lung injury models, DS NPs suppressed cytokine overexpression, accelerated re-epithelialization, and restored microvascular integrity. This work demonstrates a biomimetic hybrid platform that can integrate modulation of the inflammatory microenvironment, metabolic reprogramming, and tissue regeneration, offering a promising therapeutic strategy for early intervention in inflammation-associated tissue injuries.