5-ALA photodynamic metabolite-powered zero-waste ferroptosis amplifier for enhanced hypertrophic scar therapy

Yuan Chen, Shan Wang, Congxiu Mao, Qinyi Lu, Xingyu Zhu, Dongqi Fan, Yiping Liu, Xu Chen, Jinglei Zhan, Zixin Yang, Ping Ji (), Qingqing He () and Tao Chen ()
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Yuan Chen: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Shan Wang: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Congxiu Mao: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Qinyi Lu: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Xingyu Zhu: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Dongqi Fan: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Yiping Liu: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Xu Chen: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Jinglei Zhan: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Zixin Yang: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Ping Ji: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Qingqing He: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering
Tao Chen: Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Hypertrophic scars are a stubborn form of dermal fibrosis that impairs quality of life. Although 5-ALA-mediated photodynamic therapy holds promise, its efficacy is undermined by poor transdermal delivery and rapid metabolism into non-photosensitive heme. Here, we introduce a “zero-waste” strategy that repurposes 5-ALA-derived heme to synergistically amplify ferroptosis. This is achieved by co-encapsulating 5-ALA and baicalin within human H-ferritin, subsequently incorporated into polyvinylpyrrolidone microneedles. The resulting system enables targeted delivery to hypertrophic scar fibroblasts with pH-responsive, programmable drug release. Upon administration, 5-ALA generates protoporphyrin IX to initiate photodynamic therapy. Baicalin is then released to induce ferroptosis and synergize with the reactive oxygen species and heme accumulated during photodynamic therapy, thereby overstimulating the HO-1–heme metabolic axis. This cascade promotes the release of Fe²⁺ and CO, further amplifying ferroptotic responses. Moreover, the ferroptotic stress triggers mitophagy and mitochondrial Fe²⁺ efflux. By harnessing 5-ALA metabolic byproducts, this strategy achieved markedly prolonged anti-scar efficacy in the female rabbit ear HS tissues, surpassing that of conventional therapies.

Date: 2025
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DOI: 10.1038/s41467-025-63438-7

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