Development and preclinical evaluation of sustained-release injectable tacrolimus nanocomposite hydrogels

• Development of a nanocomposite hydrogel platform for Tacrolimus (TAC) delivery. • Nanocomposite hydrogel maintains TAC therapeutic levels and reduces burst release. • Development of a novel polyamino acid thermosensitive hydrogel for drug delivery. Tacrolimus (TAC) is a key immunosuppressant in kidney transplantation, but complex dosing, food interactions, and routine disruptions affect adherence, especially in adolescents, increasing the risk of rejection. Developing an injectable, sustained-release form could enhance adherence and pharmacokinetics. This study introduced a nanocomposite hydrogel platform for sustained TAC delivery, maintaining therapeutic levels and reducing burst release. Two strategies were developed: a thermosensitive hydrogel and a nanocomposite hydrogel. The 7-day TAC platform uses a novel thermosensitive polymer that gels under physiological conditions. We synthesized and characterized 26 polyamino acid-based polymers, including three polyaspartate types that gelled under physiological conditions. Their structure, gel transition, and safety were evaluated in vitro and in vivo. PPLA 8 -PEG 45 -PPLA 8 gels through aggregation and sheet formation. We also developed a TAC-loaded nanoparticle platform with PEG 5k -b-PCL 10k . TAC or TAC-loaded nanoparticles (TAC-NP) were incorporated into a polyester (pvlGel) or aminoGel (PPLA 8 -PEG 45 -PPLA 8 ) hydrogel and tested in rats. AminoGel showed less burst release than pvlGel with TAC. The nanocomposite hydrogel with TAC-NP significantly reduced burst release, maintaining TAC within the therapeutic window for more than 7 days. This platform offers controlled release, fills a clinical gap, and can be adapted for other diseases requiring injectable sustained-release systems.