An Apoptotic Body-Mimetic Nanoagonist for Synergistic Diabetic Wound Immunotherapy.

Abstract

Diabetic skin injury (DSI), which are challenging to heal, contribute to global economic losses exceeding US$ 250 billion annually. The impaired healing process is primarily driven by severe local inflammation, excessive oxidative stress, and restricted angiogenesis, with dysfunctional macrophage polarization being a central pathological factor. Inspired from mechanisms of apoptotic cell clearance and maintenance of tissue homeostasis in the body, herein we developed a sprayable apoptotic body-mimic nanotherapeutic with macrophage-targeting anti-inflammatory and antioxidant properties, which consisted of the 'eat me' signal, phosphatidylserine-exposing nanoliposome containing epigallocatechin gallate-magnesium ion nanocomplexes (EGCG-Mg@PSLs). Both in vitro and in vivo experiments demonstrated that macrophage-targeted EGCG-Mg@PSLs effectively alleviate inflammation, promote angiogenesis and collagen fiber formation, and accelerate wound closure. Network pharmacology analysis supported the therapeutic relevance of EGCG in DSI healing. Transcriptomic sequencing also revealed that EGCG-Mg@PSLs likely modulate macrophage behavior via the MAPK signaling pathway and metabolic reprogramming. The results indicated that apoptotic body-mimic nanotherapeutics with PS-exposing shell and metal-phenolic complex core represent a promising bio-inspired therapeutic strategy for macrophage immunotherapy for chronic diabetic wounds.