多酚碱II和IR780/PLGA纳米粒子联合递送诱导焦亡效应结合光热增强肝细胞癌免疫治疗

Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy

JOURNAL OF NANOBIOTECHNOLOGY

影响因子:12.6

分区:生物学1区 Top / 生物工程与应用微生物1区纳米科技2区

发表日期:2024 Oct 21

作者: Huating Huang, Jing Fu, Hulinyue Peng, Yuanyuan He, Aqian Chang, Huizhong Zhang, Yang Hao, Xiaohan Xu, Shiman Li, Jingxia Zhao, Jian Ni, Xiaoxv Dong

DOI: 10.1186/s12951-024-02887-6

摘要

肝细胞癌（HCC）免疫治疗的临床疗效受到肿瘤低免疫原性的显著限制。最新研究表明，焦亡和光热治疗均能有效诱导肝癌细胞的肿瘤免疫原性细胞死亡（ICD）。多酚碱II（PPII），作为Rhizoma Paridis的主要活性成分，首次被证明可以诱导肿瘤细胞焦亡；而IR780在808 nm激光激活下，将光能转化为热能，有效杀灭肿瘤。然而，PPII和IR780存在溶解度低和靶向性差等问题，极大限制了其应用。为解决这些问题，将焦亡诱导剂PPII和光敏剂IR780采用沉淀法共载于PLGA纳米粒子中，并在其表面修饰适配体AS1411，构建靶向纳米粒子（Apt/PPII/IR780-NPs）。该纳米粒子具有pH/NIR双响应智能释放特性，实现药物在肿瘤部位的靶向和控释。此外，在激光照射下能快速释放PPII诱导细胞焦亡，结合基于IR780的光热治疗，在体内外均表现出显著的协同抗肿瘤作用。该过程不仅促进树突状细胞（DCs）成熟和效应T细胞激活，从而启动适应性免疫，还能产生持久有效的免疫记忆。此外，Apt/PPII/IR780-NPs显著提升抗-PD-1疗效。综上所述，基于Apt/PPII/IR780-NPs的化疗-光热治疗能显著增强肿瘤ICD，为HCC免疫治疗提供了有前景的新策略。

Abstract

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808 nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy.