Zhu Luwen, Hu Jiahao, Wu Xiaochuan, Zhang Jucong, Xu Xinyi, Huang Xiajie, Tian Bing, Zhao Chun-Xia, Du Yongzhong, Wu Liming
Department of General Surgery, Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, P. R. China.
State Key Laboratory of Advanced Drug Delivery and Release Systems, Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China.
Nat Commun. 2025 Mar 28;16(1):3017. doi: 10.1038/s41467-025-58124-7.
Ferroptosis and pyroptosis, as emerging regulated forms of cell death capable of overcoming apoptotic resistance, demonstrate promising potential in tumor therapy. Given that iron manipulation and reactive oxygen species elevation serve as common stimuli for both processes, inducing lysosomal membrane permeabilization (LMP) with ensuing release of lysosomal contents (including iron ions and cathepsins) is anticipated to realize dual induction of ferroptosis/pyroptosis. Herein, we report a folic acid and croconaine molecule-functionalized upconversion nanoparticle (UCNP-Cro/FA) that is able to mobilize intracellular stores of endogenous iron and spatiotemporally control the lysosome-intrinsic Fenton chemistry, thereby triggering LMP-associated cell death. The process of endogenous iron mobilization occurs through two key steps: Cro-mediated coordination of abundant Fe ions within lysosomes, followed by UV-emitting upconversion core-mediated photoreduction, resulting in Fe ions release. Both in vitro and in vivo experiments show that UCNP-Cro/FA + NIR treatment effectively boost LMP by endogenous iron-mediated •OH production, ultimately triggering irreversible tumor cell death via ferroptosis and Caspase-1/GSDMD-dependent pyroptosis pathways. Moreover, this process potentiates tumor immunogenicity, holding promise for tumor immunotherapy. Overall, this work proposes a feasible tumor therapy strategy that integrates ferroptosis and pyroptosis through the efficient application and activation of endogenous iron.
铁死亡和焦亡作为新兴的可调控细胞死亡形式，能够克服细胞凋亡抗性，在肿瘤治疗中展现出了广阔的潜力。鉴于铁调控和活性氧升高是这两个过程的常见刺激因素，诱导溶酶体膜通透性增加（LMP）并随之释放溶酶体内容物（包括铁离子和组织蛋白酶）有望实现铁死亡/焦亡的双重诱导。在此，我们报道了一种叶酸和藏红花酸分子功能化的上转换纳米颗粒（UCNP-Cro/FA），它能够动员细胞内源性铁储备，并时空控制溶酶体固有的芬顿化学反应，从而触发与LMP相关的细胞死亡。内源性铁动员过程通过两个关键步骤发生：Cro介导的溶酶体内大量铁离子的配位，随后是紫外发光上转换核心介导的光还原，导致铁离子释放。体外和体内实验均表明，UCNP-Cro/FA + 近红外光处理通过内源性铁介导的•OH生成有效地促进了LMP，最终通过铁死亡和半胱天冬酶-1/ Gasdermin D依赖性焦亡途径触发不可逆的肿瘤细胞死亡。此外，这一过程增强了肿瘤免疫原性，为肿瘤免疫治疗带来了希望。总体而言，这项工作提出了一种可行的肿瘤治疗策略，即通过内源性铁的有效应用和激活来整合铁死亡和焦亡。
