Self-Strengthened PDT Coupling ROS Precise Regulation High-Penetration Microneedle for Adaptive Treatment of Pathological Scar

Pathological scars are fibrotic disorders arising from aberrant wound healing. PDT is effective but limited by a dense matrix, hypoxia, and post-PDT excessive ROS-induced secondary inflammation. To address this, a NIR-switchable ROS-regulatory liposome (ICC@Lip) with CaO₂ NPs (oxygenation to strengthen PDT) and Cu_5.4O nanozymes (ROS scavenging) was developed. In addition, inspired by <i>Cyperaceae</i> stems and triangular arrows, a highly penetrable biomimetic microneedle platform loaded with ICC@Lip and collagenase I (ICC@Lip/HPMN) was constructed to realize efficient transdermal cargo delivery and diffusion into a rigid pathological scar matrix. The puncture resistance of ICC@Lip/HPMN was only 56.4% that of conventional rectangular pyramid microneedles, with an effective puncture rate of 96% in mouse skin. <i>In vitro</i>, under NIR irradiation-mediated PDT/PTT, ICC@Lip significantly alleviated intracellular hypoxia and related fibrotic indicators, achieving a cytotoxicity rate of 93.71% against myofibroblasts─1.49-fold higher than that of the IR808 alone group (62.74%)─while reducing M2 macrophage polarization and TGF-β secretion. Notably, timely post-PDT ROS clearance decreased M1 polarization of macrophages and reduced the release of over 50% of inflammatory cytokines. In rabbit ear, a hypertrophic scar model exhibited that ICC@Lip/HPMN reduced the scar elevation index from 3 to 1.7, significantly alleviating collagen deposition and inflammation. The antifibrotic efficacies were majorly exerted through cross-downregulation of TGF-β, IL-4, and toll-like receptor signaling pathways. This study provided a promising adaptive therapeutic strategy of self-strengthened PDT coupling ROS precise regulation for pathological scars.