A Precisely Controlled Long-Acting Immunosuppression Platform Enables Prolonged Survival of Vascularized Composite Allografts

Vascularized composite allotransplantation (VCA) restores complex tissue defects but demands lifelong systemic immunosuppression. Oral tacrolimus (TAC) is limited by a narrow therapeutic window, pharmacokinetic variability, adherence challenges, and toxicity. Local delivery could mitigate these issues, yet clinical translation has been hindered by burst release, short duration, and the inability to co-deliver agents. We developed PRECISE (Programmable, REtrievable, Controlled ImmunoSuppression Encapsulator), an injectable, in-situ-forming PLGA depot that achieves long-acting, tightly controlled TAC release via structure-guided co-formulation with drug-binding agents (DBAs). GRAS small molecules (e.g., EGCG, maltotriose) identified by in silico docking and in vitro screening suppressed burst and modulated solvent efflux. Notably, rapamycin (RAPA) served dually as an mTOR inhibitor and a TAC-binding excipient, enabling synchronized dual-agent delivery. PRECISE eliminated burst in vitro and produced coordinated TAC+RAPA release with clinically compatible injectability. In rats, monthly intragraft dosing maintained systemic TAC/RAPA within the therapeutic window ([~]5-10 ng/mL) for >300 days, prolonged hindlimb allograft survival, expanded Tregs, and induced donor-specific hyporesponsiveness. Surgical retrieval of the depot triggered rapid TAC decline, demonstrating reversibility. In a stringent, fully MHC-mismatched porcine VCA model, PRECISE maintained on-target drug levels and extended graft survival beyond 90 days with minimal rejection and preserved vascular integrity. PRECISE is, to our knowledge, the first retrievable, injectable platform to deliver long-acting, dual-agent immunosuppression with controlled kinetics, rapid attainment of therapeutic steady state, and sustained graft protection. Its modular, structure-guided design enables clinical translation across VCA and solid-organ transplantation, delivering precise, durable, and safer immunosuppression.