酶指导下的生物活性分子自组装成细胞内的纳米束被认为有潜力破坏细胞膜和亚细胞结构。本文通过经典的Michael加成反应，将光敏剂吲哚菁绿（ICG）与CF4 KYp肽连接起来以制备一种碱性磷酸酶（ALP）可激活的ICG-CF4 KYp混合物。 ALP催化ICG-CF4 KYp的脱磷酸酰化，使其从小分子前体转化为坚硬的纳米纤维，这种原位纤维化引起了细胞膜的严重机械破坏。此外，ICG介导的光敏作用通过脂质过氧化导致细胞膜的额外氧化损伤。空心MnO2纳米球通过肿瘤特异性酸度/谷胱甘肽诱导的MnO2降解将ICG-CF4 KYp输送到肿瘤组织中，这是通过荧光探针和磁共振成像进行监测的。在治疗期间，损伤相关的分子模式和其他肿瘤抗原的爆发性释放有效地触发免疫细胞死亡，提高免疫刺激作用，如促进树突状细胞成熟和CD8+淋巴细胞浸润，同时限制调节性T细胞人口。综上，基于肽原位纤维化的细胞膜损伤策略具有高度的临床前景，可用于定位消除原发性、远处效应和转移性肿瘤，这可能启示更多生物启发型纳米平台用于抗癌治疗和诊断。 © 2023 Wiley-VCH GmbH。

Enzyme-instructed self-assembly of bioactive molecules into nanobundles inside cells is conceived to potentially disrupt plasma membrane and subcellular structure. Herein, an alkaline phosphatase (ALP)-activatable hybrid of ICG-CF4 KYp is facilely synthesized by conjugating photosensitizer indocyanine green (ICG) with CF4 KYp peptide via classical Michael addition reaction. ALP-induced dephosphorylation of ICG-CF4 KYp enables its transformation from small-molecule precursor into rigid nanofibrils, and such fibrillation in situ causes severe mechanical disruption of cytomembrane. Besides, ICG-mediated photosensitization causes additional oxidative damage of plasma membrane by lipid peroxidation. Hollow MnO2 nanospheres devote to deliver ICG-CF4 KYp into tumorous tissue through tumor-specific acidity/glutathione-triggered degradation of MnO2 , which is monitored by fluorescent probing and magnetic resonance imaging. The burst release of damage-associated molecular patterns and other tumor antigens during therapy effectively triggers immunogenetic cell death and improves immune stimulatory, as demonstrated by the promotion of dendritic cell maturation and CD8+ lymphocyte infiltration, as well as constraint of regulatory T cell population. Taken together, such cytomembrane injury strategy based on peptide fibrillation in situ holds high clinical promise for lesion-specific elimination of primary, abscopal, and metastatic tumors, which may enlighten more bioinspired nanoplatforms for anticancer theranostics.© 2023 Wiley-VCH GmbH.