自噬是降低肿瘤光疗（包括PTT和PDT）疗效的重要因素。精准调控肿瘤细胞自噬是提高PTT/PDT抗肿瘤效率的新策略。该项目旨在构建一种肿瘤激活的自噬调节因子，以有效阻断PTT/PDT诱导的自噬，实现对肿瘤光疗的协同增敏。为了实现这一目标，我们首先合成了转铁蛋白（Tf）仿生矿化纳米碲（Tf-Te）作为光敏剂，然后利用二硫键重建技术诱导Tf-Te自组装。同时负载自噬抑制剂羟氯喹（HCQ）和Tf携带的铁离子，制备肿瘤响应性药物储库Tf-Te/HCQ。 Tf-Te/HCQ通过“自我引导系统”进入乳腺癌细胞后，在近红外激光照射下可产生高热和ROS，有效诱导PTT/PDT效应。同时，二硫键在 GSH 的作用下断裂，纳米颗粒分解并在固定点释放出 Fe2 和 HCQ。它们同时诱导溶酶体碱化和渗透压升高，有效抑制自噬，协同增强光疗的治疗效果。体内抗肿瘤结果证明，Tf-Te/HCQ对4T1荷瘤小鼠的抑瘤率高达88.6%。这种多功能药物输送系统可能为更精确、更有效的肿瘤光疗提供新的替代方案。© 2024 作者。

Autophagy is an important factor in reducing the efficacy of tumor phototherapy (including PTT and PDT). Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT. This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy. To achieve this goal, we first synthesized TRANSFERRIN (Tf) biomimetic mineralized nano-tellurium (Tf-Te) as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly. The autophagy inhibitor hydroxychloroquine (HCQ) and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ. After entering breast cancer cells through the "self-guidance system", Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation, to efficiently induce PTT/PDT effect. Meanwhile, the disulfide bond broke down in response to GSH, and the nanoparticles disintegrated to release Fe2+ and HCQ at fixed points. They simultaneously induce lysosomal alkalinization and increased osmotic pressure, effectively inhibit autophagy, and synergistically enhance the therapeutic effect of phototherapy. In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6% on 4T1 tumor-bearing mice. This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.© 2024 The Authors.