Zhang Xu, Zang Zhongsheng, Liang Zhenguo, Xu Xiaoyu, Zheng Jinling, Liang Na, Shabiti Shayibai, Wang Zixi, Yu Shiwen, Wang Yujue, Liu Chenli, Li Wenjun, Cai Lintao
Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China.
University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
ACS Nano. 2025 Feb 18;19(6):6437-6453. doi: 10.1021/acsnano.4c16740. Epub 2025 Feb 4.
"Living therapeutic carriers" present a promising avenue for cancer research, but it is still challenging to achieve uniform and durable distribution of payloads throughout the solid tumor owing to the tumor microenvironment heterogeneity. Herein, a living drug sprinkle biohybrid (YB1-HCNs) was constructed by hitching acid/enzyme-triggered detachable nanoparticles (HCNs) backpack on the surface of metabolic oligosaccharide-engineered oncolytic bacteria YB1. Along with the process of tumor penetration by bacterial hypoxia navigation, YB1-HCNs responsively and continuously release HCNs, achieving a uniform distribution of loaded agents throughout the tumor. Upon successive irradiation of laser and ultrasound (US), the HCNs can separately generate type II and type I ROS for superior sono-photodynamic therapy (SPDT), which enables HCNs to synergize with YB1 for a satisfactory therapeutic effect in both superficial normoxic and deep hypoxic regions of the tumor. After a single dose, this efficient combination realized 98.3% primary tumor inhibition rate and prolonged survival of mice for 90 days with no recurrence, further inducing a powerful immunological memory effect to completely suppress tumor rechallenge in cured mice. Such a bacterial hybridization vector enables optimization of the spatial distribution of YB1 and HCNs, providing an innovative strategy to maximize therapeutic outcomes and evoke durable antitumor immunity.
“活体治疗载体”为癌症研究提供了一条有前景的途径，但由于肿瘤微环境的异质性，要在实体瘤中实现有效载荷的均匀且持久分布仍具有挑战性。在此，通过将酸/酶触发的可分离纳米颗粒（HCNs）“背包”挂载在代谢寡糖工程化溶瘤细菌YB1的表面，构建了一种活体药物喷洒生物杂交体（YB1-HCNs）。随着细菌通过缺氧导航实现肿瘤穿透的过程，YB1-HCNs响应并持续释放HCNs，从而使负载的药物在整个肿瘤中实现均匀分布。在连续进行激光和超声（US）照射后，HCNs可分别产生II型和I型活性氧用于高效的声动力疗法（SPDT），这使得HCNs能够与YB1协同作用，在肿瘤的浅表常氧区域和深部缺氧区域均产生令人满意的治疗效果。单次给药后，这种高效组合实现了98.3%的原发性肿瘤抑制率，并使小鼠存活期延长90天且无复发，进一步诱导了强大的免疫记忆效应，从而完全抑制治愈小鼠的肿瘤再激发。这种细菌杂交载体能够优化YB1和HCNs的空间分布，为最大化治疗效果和激发持久抗肿瘤免疫提供了一种创新策略。
