Hypoxia Alleviation Enhances the Efficacy of 5‐Fluorouracil in Hypertrophic Scar Therapy via an Oxygen‐Popping Microneedle System

Abstract Hypertrophic scars (HS) result from aberrant wound healing, often leading to disfigurement and functional impairment. Hypoxia is a prominent feature of HS; however, its impact on therapeutic efficacy remains unexplored, presenting a potential pathway for advancing HS treatments. Here, hypoxia is identified as a limiting factor in the efficacy of 5‐fluorouracil (5‐Fu), a widely used clinical drug for HS. At the gene expression level, 5‐Fu response genes associated with the mitotic cell cycle, such as BUB1 and SPAG5, fail to be downregulated under hypoxia in human HS fibroblasts, contributing to the altered cytotoxic response. To address this limitation, an oxygen‐popping microneedle (MN) system is developed to alleviate hypoxia in HS and enhance 5‐Fu‐based therapy. Inspired by the gas‐release mechanism of Pop Rocks candy, high‐pressure oxygen‐trapping particles (HOTP) are formulated and integrated into a core–shell MN platform, enabling localized co‐delivery of oxygen and 5‐Fu. The popping release of oxygen also facilitates 5‐Fu penetration into dense HS tissue. In vivo studies provide strong evidence that the MN system effectively mitigates hypoxia, significantly enhancing the therapeutic efficacy of 5‐Fu. This research presents an innovative strategy for optimizing HS therapy by alleviating hypoxia, with the potential to inform future advancements in HS treatment.