Cross-KingdommiR5054 Delivery via Polygonum cuspidatum -Derived Nanoparticles Enhances Burn Wound Healingby Regulating Microvascular Environment

Abstract Deep partial-thickness burns are characterized by a self-perpetuating cycle of oxidative stress and inflammation that severely impedes healing. Here, we identified Polygonum cuspidatum-derived nanoparticles (PDNs) as a multifaceted nanotherapeutic that breaks this pathogenic loop. We found that PDNs coencapsulate immediate radical-scavenging metabolites with a functional microRNA, miR5054. Upon endothelial delivery, miR5054 directly targets and silences Keap1 mRNA, leading to sustained activation of the Nrf2 antioxidant pathway. This Nrf2 activation cross-inhibits the pro-inflammatory NF-κB signaling axis in endothelium. The resultant dual amelioration of oxidative and inflammatory stress potently reprograms the wound immune microenvironment, polarizing macrophages toward a pro-healing M2 phenotype. In burn models, PDNs accelerated wound closure, enhanced collagen remodeling, and fostered a Nrf2-high, M2-dominant pro-regenerative niche. The therapeutic effect of PDNs was abolished by a complementary-sequence inhibitor of miR5054, establishing its indispensable role. Furthermore, a synthetic miR5054 mimic recapitulated these benefits, while a thermosensitive hydrogel formulated for PDN delivery enhanced skin penetration and healing efficacy. Our work unveils PDNs as a natural combinatorial therapy that codelivers chemical and genetic components to simultaneously disrupt the oxidative-inflammatory cascade in burns, presenting a translatable, biomimetic strategy for advanced wound management.