Liu Chang, Yang Canyu, Jiang Xiuxian, Lu Xiang, Huang Xiaoyu, Wei Junchao, Nie Di, Wang Yang, Guo Shiyan, Zheng Ying, Pan Chao, Gan Yong
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
ACS Nano. 2025 Jul 8;19(26):23760-23777. doi: 10.1021/acsnano.5c03862. Epub 2025 Jun 26.
Cancer immunotherapy, including immune checkpoint blockade (ICB), often has limited efficacy due to inadequate neoantigen exposure. Although neoantigen vaccines can enhance immune sensitization, their clinical application is hindered by high identification costs and tumor heterogeneity. Alternatively, heteroantigen presentation by cancer cells offers a promising strategy to improve immunotherapy. Herein, hyaluronic acid (HA)-modified bacterial membrane vesicles were developed as heteroantigen reservoirs (HLGV) and then further loaded with PD-L1 siRNA (siPD-L1) for immune checkpoint blockade. Intracellularly, HLGV released heteroantigens and siPD-L1 into the cytoplasm via early endosomal membrane fusion. The heteroantigens were presented by MHC class I molecules, while siPD-L1 escaped lysosomal degradation and effectively silenced PD-L1 expression. When administered peritumorally, the synergistic therapeutic effect of heteroantigen presentation and ICB significantly inhibited both subcutaneous CT-26 tumors and distant metastases. For colorectal cancer immunotherapy, HLGV@siPD-L1 was encapsuled into chondroitin sulfate hydrogel microspheres (HEBV@siPD-L1) and administered through oral gavage. Ultimately, HEBV@siPD-L1 increased the infiltration of macrophages and CD8 T cells and effectively suppressed the growth of orthotopic colorectal cancer, with the tumor inhibition rate reaching 91.6%. These findings demonstrated the potential of bacterial membrane vesicles as heteroantigen reservoirs to activate antitumor immune responses, which could further synergize with ICB for promoted immune efficacy.
癌症免疫疗法，包括免疫检查点阻断（ICB），由于新抗原暴露不足，疗效往往有限。尽管新抗原疫苗可以增强免疫致敏作用，但其临床应用受到高鉴定成本和肿瘤异质性的阻碍。另外，癌细胞呈递异源抗原为改善免疫疗法提供了一种有前景的策略。在此，透明质酸（HA）修饰的细菌膜囊泡被开发为异源抗原储存库（HLGV），然后进一步装载PD-L1小干扰RNA（siPD-L1）用于免疫检查点阻断。在细胞内，HLGV通过早期内体膜融合将异源抗原和siPD-L1释放到细胞质中。异源抗原由MHC I类分子呈递，而siPD-L1逃避溶酶体降解并有效沉默PD-L1表达。当瘤周给药时，异源抗原呈递和ICB的协同治疗效果显著抑制了皮下CT-26肿瘤和远处转移。对于结直肠癌免疫疗法，HLGV@siPD-L1被封装到硫酸软骨素水凝胶微球（HEBV@siPD-L1）中并通过灌胃给药。最终，HEBV@siPD-L1增加了巨噬细胞和CD8 T细胞的浸润，并有效抑制了原位结直肠癌的生长，肿瘤抑制率达到91.6%。这些发现证明了细菌膜囊泡作为异源抗原储存库激活抗肿瘤免疫反应的潜力，其可进一步与ICB协同作用以提高免疫疗效。
