以紫杉醇（PTX）为基础的化疗仍然是治疗肺癌的主要方法，但系统毒性限制了其使用。嵌合抗原受体T（CAR-T）细胞源外泌体含有针对肿瘤的抗原受体和细胞毒性颗粒（谷胱甘肽B和穿孔素），被认为是PTX的可能输送载体。然而，外泌体的低药物负载能力和肝靶性特性成为其应用于非肝癌的障碍。在这里，我们设计了名为Lip-CExo@PTX的混合纳米囊泡，通过将双特异性CAR-T细胞源外泌体与靶向肺的脂质体融合，用于肺癌的免疫化疗。由于脂质体的肺靶向能力，超过95％的经静脉注射的Lip-CExo@PTX积累在肺组织中。此外，在抗MSLN的单链变量片段（scFv）的帮助下，Lip-CExo@PTX内的PTX和细胞毒性颗粒进一步输送至MSLN阳性肿瘤。值得注意的是，Lip-CExo@PTX上的抗PD-L1 scFv阻断了肿瘤上的PD-L1，以避免T细胞耗竭并促进PTX引起的免疫原性细胞死亡。此外，Lip-CExo@PTX延长了CT-26转移性肺癌模型中带瘤小鼠的存活时间。因此，Lip-CExo@PTX可以通过顺序靶向输送将PTX输送至肿瘤细胞，并增强抗肿瘤作用，为肺癌的免疫化疗提供了一种有前景的策略。

Paclitaxel (PTX)-based chemotherapy remains the main approach to treating lung cancer but systemic toxicity limits its use. As chimeric antigen receptor-T (CAR-T) cell-derived exosomes contain tumor-targeted CARs and cytotoxic granules (granzyme B and perforin), they are considered potential delivery vehicles for PTX. However, the low drug-loading capacity and hepatotropic properties of exosomes are obstacles to their application to extrahepatic cancer. Here, a hybrid nanovesicle named Lip-CExo@PTX was designed for immunochemotherapy of lung cancer by fusing exosomes derived from bispecific CAR-T cells targeting both mesothelin (MSLN) and programmed death ligand-1 (PD-L1) with lung-targeted liposomes. Due to the lung-targeting ability of the liposomes, over 95% of intravenously administered Lip-CExo@PTX accumulated in lung tissue. In addition, with the help of the anti-MSLN single-chain variable fragment (scFv), the PTX and cytotoxic granules inside Lip-CExo@PTX were further delivered into MSLN-positive tumors. Notably, the anti-PD-L1 scFv on Lip-CExo@PTX blocked PD-L1 on the tumors to avoid T cell exhaustion and promoted PTX-induced immunogenic cell death. Furthermore, Lip-CExo@PTX prolonged the survival time of tumor-bearing mice in a CT-26 metastatic lung cancer model. Therefore, Lip-CExo@PTX may deliver PTX to tumor cells through sequential targeted delivery and enhance the antitumor effects, providing a promising strategy for immunochemotherapy of lung cancer.