Orthogonal upconversion supramolecular microneedles promote endogenous ferroptosis in keloids

<b>Background:</b> Keloids represent a type of tumor-like fibroproliferative disease, which can not only cause aesthetic damage but also threaten health. Current therapies often lack precision and efficacy, necessitating minimally invasive and targeted strategies. <b>Methods:</b> This study developed orthogonal upconversion supramolecular microneedles (OUSMNs) integrated with surface-functionalized upconversion nanoparticles (UCNPs) for intelligent keloid therapy. The UCNPs were functionalized by the ferritin homing peptide (HKN₁₅) and a photosensitizer (rose Bengal), which could target keloid fibroblast (KF) and generate singlet oxygen (¹O₂), thereby inducing endogenous ferroptosis. Mechanistic effects on PI3K-AKT, mTOR, and ferroptosis pathways were analyzed by transcriptome analysis and rescue experiments. <b>Results:</b> The OUSMNs are strong and tough to effectively penetrate the fibroproliferative tissue, and can rapidly dissolve in keloids within 60 s, which makes the UCNPs easy to target the KF by the ferritin-homing peptide HKN₁₅ on the particle surface. The targeting process can be tracked by the red-color upconversion emission under 980 nm laser. On the other hand, upon 808 nm laser irradiation, the UCNPs can lead to the generation of ¹O₂. The ¹O₂ not only result in endogenous ferroptosis by destroying the ferritin, but also give rise to synergistic photodynamic therapy that can effectively combat keloids through inhibiting the PI3K-AKT and mTOR pathways while activating the ferroptosis pathway. <b>Conclusions:</b> The proposed OUSMNs promise practical applications for minimally invasive, precise and intelligent keloid therapy.