Self-Driving and Detachable Lab-Microrobots Tailor Drug Delivery for Closed-Loop Stimulation of the Antitumor Immune Cycle.

Abstract

Hypoxia arises in most solid tumors with insufficient blood flow, which hinders the delivery and efficacy of therapeutic agents to tumors. In this work, utilizing anaerobic bacteria capable of seeking out hypoxic areas for flourishing, we constructed a liposome-anchored anaerobic bacteria (Lab)-microrobot for self-driving and detachable delivery of immunity activators to tumor sites, thereby orchestrating antitumor immune responses. Super-resolved structured illumination microscopy images visualized that Lab-microrobots were assembled from liposomes studding on the capsid of engineered Salmonella. Notably, these self-driving Lab-microrobots exhibited an average velocity of 0.80 ± 0.72 μm/s and possessed robust tumor tropism tracked by fluorescence microfluidics. Intriguingly, live-cell imaging analysis demonstrated Lab-microrobots could intentionally detach into two components upon reaching tumor sites, enabling dual-targeted delivery of the ICD inducer and PD-L1 inhibitor to tumor cells, while Salmonella served as an immune enhancer to macrophages. Consequently, in primary and metastatic melanoma models, Lab-microrobots facilitated the release of ICD-associated danger signals to enhance dendritic cell maturation and subsequently elicit immune activation, including increasing cytotoxic T lymphocyte infiltration into tumors while decreasing Tregs. By enabling self-driving and dual-targeted delivery, Lab-microrobots create a closed-loop stimulation of the antitumor immune cycle, offering a tailored drug delivery platform for strengthening cancer immunotherapy.