Orthogonal upconversion nanocarriers for combined photodynamic therapy and precisely triggered gene silencing in combating keloids

Keloids are pathological scars characterized by excessive fibroblast proliferation, abnormal collagen deposition, and chronic inflammation, which often result in high recurrence rates and limited treatment success. Targeting BACH1 with gene therapy has shown promise in regulating fibroblast activity and reducing inflammation. However, effective delivery systems for targeted gene therapy in keloids remain a major challenge. Here, we develop a novel nanocarrier platform based on orthogonal upconversion nanoparticles (OUNCs) to achieve spatiotemporal silencing of BACH1 and combined photodynamic therapy (PDT). The OUNCs are composed of orthogonal upconversion nanoparticles (UCNPs), photosensitizer (Rose Bengal), ROS-sensitive diselenide bonds (SeSe), therapeutic siBACH1, and an active targeting moiety (hyaluronic acid) to specifically target keloid fibroblasts (KFs). We demonstrate that the OUNCs can effectively induce KFs apoptosis, inhibit KFs proliferation, and reduce M2 macrophages recruitment by modulating the Rap1/MEK/ERK signaling pathway. Our study represents a breakthrough in precision therapy for keloids, providing a promising platform that integrates siBACH1-based gene therapy with NIR light-triggered PDT.