Zhao Xiaoxi, Zhong Qinjie, Abudouaini Naibijiang, Zhao Yan, Zhang Jibin, Tan Guozhu, Miao Guifeng, Wang Xiaowu, Liu Jianqiang, Pan Ying, Wang Xiaorui
Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong 510515, China.
Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
Biomacromolecules. 2025 May 12;26(5):3065-3083. doi: 10.1021/acs.biomac.5c00140. Epub 2025 Apr 8.
Photodynamic therapy (PDT) has emerged as a promising modality for cancer treatment, but its clinical application is constrained by unexpected phototoxicity arising from nonspecific photosensitizer activation and their "always-on" nature. Herein, we developed a switchable nanophotosensitizer, poly(cation-π) nanoparticles (NP), which achieves supramolecular assembly through cation-π interactions. By coupling choline cationic moieties with aromatic photosensitizers (ZnPc), the polymer facilitates self-assembly driven by cation-π interactions for NP engineering. Surprisingly, the photoactivity of ZnPc was completely quenched upon complexation via cation-π interactions, thereby significantly avoiding skin phototoxicity. Upon targeting tumor cells, NP undergoes a GSH-responsive degradation process that weakens cation-π interactions, leading to spontaneous restoration of photoactivity and amplifying tumor immunogenic pyroptosis. In vivo studies demonstrated that NP achieved a high tumor inhibition rate of 84% while effectively avoiding skin phototoxicity. This work provides a novel perspective for enhancing the safety and efficacy of PDT-based tumor treatment.
光动力疗法（PDT）已成为一种很有前景的癌症治疗方式，但其临床应用受到非特异性光敏剂激活及其“常开”性质所产生的意外光毒性的限制。在此，我们开发了一种可切换的纳米光敏剂，聚（阳离子-π）纳米颗粒（NP），它通过阳离子-π相互作用实现超分子组装。通过将胆碱阳离子部分与芳香族光敏剂（ZnPc）偶联，该聚合物促进了由阳离子-π相互作用驱动的自组装以用于NP工程。令人惊讶的是，ZnPc的光活性在通过阳离子-π相互作用络合后完全淬灭，从而显著避免皮肤光毒性。靶向肿瘤细胞后，NP经历谷胱甘肽响应性降解过程，削弱阳离子-π相互作用，导致光活性自发恢复并放大肿瘤免疫原性细胞焦亡。体内研究表明，NP实现了84%的高肿瘤抑制率，同时有效避免了皮肤光毒性。这项工作为提高基于PDT的肿瘤治疗的安全性和有效性提供了新的视角。
