Beyond Material Dominance: A Coevolutionary Approach to the “Real” IVIVC of PLGA Microspheres

ABSTRACT Thorough understanding and accurate prediction of in vivo drug release are essential for developing long‐acting microsphere systems. However, the fate of microspheres after prolonged tissue residence and the regulatory role of physiological factors remain unclear, hindering elucidation of release mechanisms. Herein, the dynamic evolution of microsphere depots and associated microenvironmental changes were studied. Beyond poly(lactic‐co‐glycolic acid) (PLGA) and API effects, microsphere depot behavior is partly regulated by conserved biological processes, with skeletal muscle and subcutaneous tissue employing distinct adaptive strategies to restore homeostasis. Using these insights, we developed the in vivo release predictive models (IVRPMs) that establish a true IVIVC for naltrexone PLGA microspheres. The IVRPMs demonstrated broad applicability across microspheres with different APIs and PLGA types, and showed promising translational potential in beagle and human studies. This study shifts the research paradigm from “material‐dominated release” to “organism‐material coevolution”, addressing a key question in depot formulation fate.