Programmable multifunctional microrobots for synergistic cuproptosis-immunotherapy

Abstract Oral microrobots as drug carriers have shown great promise in enhancing the therapeutic efficacy of colorectal cancer (CRC). However, existing platforms frequently lack the programmable temporal precision required to execute complex, multi-stage dosing regimens. Here, we report a programmable temporal-responsive microrobot (PTRM) that autonomously navigates across the gastric acid barrier under external magnetic guidance to execute a sequential drug-release program at orthotopic tumor sites. The PTRM is engineered with a logic-gated architecture, featuring a spatially specific shell for gastric-resistant shielding and exclusive intestinal pH-triggered activation. The system’s internal ‘timer’ is governed by the precise modulation of crosslinking densities within its dual gelatin cores, enabling finely-tuned biphasic release kinetics. Phase 1 executes the programmed release of elesclomol to induce tumor cell cuproptosis, successfully priming the tumor microenvironment (TME) by recruiting infiltrating immune cells. Following a precisely tuned 5.5 h interval, Phase 2 triggers the release of PD-1 inhibitors to activate these cells, thereby amplifying immunogenic cell death (ICD). This orchestrated sequential cytotoxicity achieved a 76% remission rate in an orthotopic CRC mouse model. Furthermore, the PTRM architecture is highly scalable, accommodating up to six-core configurations for multi-phase release—establishing a versatile robotic platform for complex combinatorial therapeutic strategies against recalcitrant cancers.