Liu Xu, Zhang Junlei, Guo Xuemeng, Huang Jiaxin, Lou Zeliang, Zhao Xiaoqi, Lin Qing, Li Xiang, You Jian, Luo Lihua
College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China.
College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China; Zhejiang-California International Nanosystems Institute, Zhejiang University, Hangzhou 310058, PR China; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, PR China.
J Control Release. 2023 Oct 28. doi: 10.1016/j.jconrel.2023.10.037.
Photo-immunotherapy is a promising strategy for the treatment of malignancies; however, its efficacy is often limited by the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME). TME is typically deficient in L-arginine (L-Arg), which negatively impacts T cell survival and function. To address this issue, we developed a novel drug delivery system based on the multi-vesicular liposomes (MVLs) loaded with photosensitizer indocyanine green (ICG) and L-Arg (R), named R-ICG@MVLs. Under near-infrared (NIR) light irradiation, the PDT-mediated cascade reaction of reactive oxygen species (ROS) could oxidize a portion of L-Arg to generate NO, thereby inducing immunogenic tumor cell death (ITCD) and stimulating anti-tumor immune responses, including antigen-presenting cells (APCs) recruitment and T cells activation. Subsequently, R-ICG@MVLs continued to release L-Arg, which improved the immunosuppressive TME, providing nutritional support for the tumor-infiltrating T cells and thus enhancing their anti-tumor efficacy. Additionally, the photo-thermal effect of ICG could accelerate the membrane rearrangement of R-ICG@MVLs and produce multiple drug-loaded nanovesicles, thus enabling the NIR-controlled accelerated drug release. The formation of drug-loaded nanovesicles led to deeper penetration and widened the range of ICD and TME improvement, achieving a "shrapnel effect". In conclusion, our strategy realized the dual effects of immune activation and nutrition support, which might provide a clinically applicable reference for tumor immunotherapy.
光免疫疗法是一种治疗恶性肿瘤的有前景的策略；然而，其疗效常常受到肿瘤免疫原性低和免疫抑制性肿瘤微环境（TME）的限制。TME通常缺乏L-精氨酸（L-Arg），这对T细胞的存活和功能产生负面影响。为了解决这个问题，我们开发了一种基于多泡脂质体（MVL）的新型药物递送系统，该脂质体负载有光敏剂吲哚菁绿（ICG）和L-Arg（R），命名为R-ICG@MVL。在近红外（NIR）光照射下，光动力疗法（PDT）介导的活性氧（ROS）级联反应可氧化一部分L-Arg以产生一氧化氮（NO），从而诱导免疫原性肿瘤细胞死亡（ITCD）并刺激抗肿瘤免疫反应，包括抗原呈递细胞（APC）募集和T细胞活化。随后，R-ICG@MVL持续释放L-Arg，改善免疫抑制性TME，为肿瘤浸润性T细胞提供营养支持，从而增强其抗肿瘤疗效。此外，ICG的光热效应可加速R-ICG@MVL的膜重排并产生多个载药纳米囊泡，从而实现近红外控制的加速药物释放。载药纳米囊泡的形成导致更深的渗透并扩大了ICD和TME改善的范围，实现了“榴霰弹效应”。总之，我们的策略实现了免疫激活和营养支持的双重作用，这可能为肿瘤免疫治疗提供临床应用参考。
