光动力疗法（PDT）作为一种非侵入性和时空可控的模式，在癌症治疗方面展现了巨大的潜力。然而，反应性氧化物（ROS）产生的有效性受限于光敏剂的疏水特性和聚集引起猝灭（ACQ）。因此，我们设计了一种ROS自激活的纳米系统（以聚硫杂环乙烷做为基质，侧链上接上光敏剂苤叶卟啉A（Ppa），简称PTKPa）来抑制ACQ并增强PDT的效果。具体的自激活过程是利用激光照射PTKPa产生ROS作为激活剂，加速聚硫杂环乙烷的裂解从而释放出Ppa。这进一步产生大量的ROS，加速了PTKPa的降解，增强了PDT的效果。此外，这些丰富的ROS可以放大PDT诱导的氧化应激反应，对肿瘤细胞造成不可逆转的损伤，并实现免疫原性细胞死亡（ICD），从而提高光动力免疫治疗的效果。这些发现为通过ROS自激活策略提高癌症光动力免疫治疗提供了新的思路。此外，本研究还描述了一种利用ROS响应性自激活的聚硫杂环乙烷共轭苤叶卟啉A（Ppa）的方法，可以抑制聚集引起猝灭（ACQ）并增强光动力免疫治疗。在660nm激光照射的情况下，共轭Ppa产生ROS作为触发剂，从而引发聚硫杂环乙烷的降解和释放出Ppa，产生大量的ROS，对肿瘤细胞产生氧化应激反应并实现免疫原性细胞死亡（ICD）。本研究为提高癌症光动力治疗的效果提供了有前景的解决方案。opyright © 2023. Elsevier Ltd.的出版。

Photodynamic therapy (PDT), as a non-invasive and spatiotemporally controllable modality, exhibits great potential in cancer treatment. However, the efficiency of reactive oxygen species (ROS) production was restricted to the hydrophobic characteristics and aggregation-caused quenching (ACQ) of photosensitizers. Herein, we designed a ROS self-activatable nano system (denoted as PTKPa) based on poly(thioketal) conjugated with photosensitizers (PSs) pheophorbide A (Ppa) on the polymer side chains for suppressing ACQ and enhancing PDT. The process of self-activation is that ROS, which is derived from laser irradiated PTKPa, as an activating agent accelerates poly(thioketal) cleavage with the release of Ppa from PTKPa. This in turn generates abundant ROS, accelerates degradation of the remaining PTKPa and amplifies the efficacy of PDT with more tremendous ROS generated. Moreover, these abundant ROS can amplify PDT-induced oxidative stress, cause irreversible damage to tumor cells and achieve immunogenic cell death (ICD), thereby boosting the efficacy of photodynamic-immunotherapy. These findings provide new insights into ROS self-activatable strategy for enhancing cancer photodynamic- immunotherapy. STATEMENT OF SIGNIFICANCE: This work described an approach to utilize ROS-responsive self-activatable poly(thioketal) conjugated with pheophorbide A (Ppa) for suppressing aggregation-caused quenching (ACQ) and enhancing photodynamic-immunotherapy. The ROS, generated from the conjugated Ppa upon 660nm laser irradiation, as a triggering agent which initiates the release of Ppa with poly(thioketal) degradation. That in turn generates abundant ROS and facilitates degradation of the remaining PTKPa, resulting in oxidative stress to tumor cells and achieving immunogenic cell death (ICD). This work provides a promising solution to improve tumor photodynamic therapeutic effects.Copyright © 2023. Published by Elsevier Ltd.