Autonomous Hydrogel Actuators Programmed by Endogenous Biochemical Logic for Dual-Stage Morphing and Drug Release

Designing soft materials that autonomously respond to complex physiological environments remains a fundamental challenge in biomedical systems engineering. Here, we report on a 3D-printed hybrid protein-polymer hydrogel actuator that operates via endogenous biochemical logic, enabling fully autonomous dual-stage shape morphing and enzyme-triggered drug release in gastric-mimicking environments. The actuator comprises a bilayer structure: an active layer based on bovine serum albumin-poly (ethylene glycol) diacrylate (BSA-PEGDA), and a passive PEGDA layer. In acidic gastric fluid, the BSA-PEGDA layer undergoes rapid conformational swelling, followed by delayed softening from pepsin-mediated degradation, autonomously driving reversible shape transitions without manual intervention. By embedding doxorubicin (DOX) within the BSA-PEGDA hydrogel network, the system achieves site-specific, enzyme-gated drug release that is tunable using pepstatin A as a biochemical inhibitor. High-resolution digital light processing (DLP) printing enables the fabrication of complex autonomous actuators and microneedle-equipped grippers capable of mucosal adhesion, catch-and-release behavior, and controlled delivery. This work establishes a materials design strategy where biochemical cues are used as programmable inputs to drive mechanical and therapeutic outputs, offering a robust platform for bioresponsive soft robotics and in situ drug delivery.