Bidirectional thermo-switch hydrogels with size-selective diffusion for programmable delivery of medicines

The precise manipulation of molecular transport in physiological environments remains a central challenge for stimulus-responsive drug delivery. Here, Bidirectional Thermo-Switch (BiTS) hydrogels encode temperature-dependent release behavior within a single poly(N-isopropylacrylamide) (pNIPAam) network integrating imidazolium ionic domains and imidazolium-based ionic crosslink junctions. This architecture yields a mechanically robust yet thermally reconfigurable matrix with transitions tuned to near-physiological temperatures. Cooling induces hydration-driven mesh expansion, enabling enhanced release of the macromolecular immunosuppressant cyclosporine A (CsA). In contrast, mild heating relevant to inflamed or hyperthermic tissue contracts the network, suppressing CsA permeation while accelerating squeeze-driven release of the smaller anti-inflammatory drug ketoprofen (Keto). Spectroscopic and thermal characterization confirms network integration, and swelling and release studies demonstrate reversible, repeatable two-way transport under thermal cycling, including ex vivo Franz-cell permeation of co-loaded therapeutics. BiTS hydrogels maintain high cytocompatibility and sustain immunoregulatory activity, evidenced by reduced T cell proliferation and IL-2 secretion. Collectively, the BiTS platform enables temperature-dependent inversion of molecular transport within a single hydrogel matrix, establishing a thermo-responsive dual-regime drug delivery system.