Physiologically controlled release from an in situ forming liposomal depot.

Poor treatment adherence, often referred to as the "silent epidemic," is a growing global issue that significantly contributes to preventable illness, premature death, and rising healthcare costs. Among compliance-enhancing strategies, controlled-release depots designed for intermediate treatment cycles represent a suitable approach, particularly in contexts where frequent dosing is impractical. Current long-acting injectable formulations, though, are often hindered by challenges in injectability, delayed onset, and complex manufacturing. Here, we present a thermoresponsive, in situ forming liposomal depot (TILD) designed to modulate the release of membrane-associated drugs following subcutaneous administration. Using buprenorphine as a model analgesic, we demonstrate that TILD responds to subcutaneous divalent cations with immediate surface-drug release and to body temperature with sustained diffusion through a fluidized bilayer. Molecular simulations guided the system design, and structural and colloidal characterizations validated its responsiveness to physiological cues. In vivo, TILD formed stable depots and maintained therapeutic drug levels for up to four days in both rats and Beagle dogs. Pharmacodynamics studies in rats confirmed the delivery of prolonged analgesia.