肿瘤细胞治疗研究
英文原题：Engineering BiTE-inspired IPSC-exosomes to potentiate CAR-T cell therapy against lung cancer.
CAR-T（CAR-T）细胞疗法在实体瘤中面临关键障碍，包括浸润不良、T 细胞耗竭和免疫抑制微环境，导致缓解率低于 10%。
CAR-T（CAR-T）细胞疗法在实体瘤中面临关键障碍，包括浸润差、T细胞耗竭和免疫抑制微环境，导致应答率低于10%。在此，我们利用诱导多能干细胞来源的外泌体（IEXOs）构建了一种可吸入纳米平台，该平台展示双特异性PD-1/间皮素（MSLN）单链可变片段（scFv），并负载吲哚-3-丙酸（IPA）以进行代谢重编程。IEXOs表现出高产率和内在抗肿瘤特性，可抑制Lewis肺癌（LLC）细胞增殖和迁移。负载IPA的双特异性外泌体（BIEXO@IPA）通过雾化实现了高效肺部递送，在原位肺癌模型中肿瘤细胞特异性摄取率达79.3%，而脂质体为47.9%。BIEXO@IPA治疗使肿瘤负荷降低87.9%，并在80天时实现80%生存率。在机制上，BIEXO@IPA通过双特异性结合将PD-1+ T细胞与MSLN+肿瘤细胞桥接，同时扩增祖细胞耗竭T（Tpex）细胞并减少调节性T细胞。与CAR-T细胞联合使用时，BIEXO@IPA实现66.7%完全缓解，80天时生存率达100%，并对肿瘤再攻击具有83.3%的抵抗能力。安全性评估显示毒性极低。这一BIEXO@IPA平台代表了一种可规模化、临床可转化的策略，通过协同多模式免疫调节解决了CAR-T在实体瘤中的根本局限性。
Chimeric antigen receptor T (CAR-T) cell therapy faces critical barriers in solid tumors, including poor infiltration, T cell exhaustion, and immunosuppressive microenvironments, resulting in response rates below 10%. Herein, we engineered an inhalable nanoplatform using induced pluripotent stem cell-derived exosomes (IEXOs) displaying bispecific PD-1/mesothelin (MSLN) single-chain variable fragments (scFv) and loaded with indole-3-propionic acid (IPA) for metabolic reprogramming. IEXOs demonstrated high yield and intrinsic antitumor properties, inhibiting Lewis lung carcinoma (LLC) cell proliferation and migration. The bispecific exosomes loaded with IPA (BIEXO@IPA) achieved efficient pulmonary delivery via nebulization with 79.3% tumor cell-specific uptake versus 47.9% for liposomes in orthotopic lung cancer models. BIEXO@IPA treatment reduced tumor burden by 87.9% and achieved 80% survival at 80 days. Mechanistically, BIEXO@IPA bridged PD-1 + T cells to MSLN + tumor cells through bispecific engagement while expanding progenitor exhausted T (Tpex) cells and reducing regulatory T cells. When combined with CAR-T cells, BIEXO@IPA achieved 66.7% complete remission with 100% survival at 80 days and 83.3% resistance to tumor rechallenge. Safety assessments revealed minimal toxicity. This BIEXO@IPA platform represents a scalable, clinically translatable strategy that addresses fundamental CAR-T limitations in solid tumors through synergistic multimodal immunomodulation.
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