High drug-loaded supramolecular microgels enabled by controlled in-droplet self-assembly for adaptive treatment of inflammatory arthritis

Supramolecular hydrogels derived from low-molecular-weight gelators (LMWGs) have attracted considerable interest in drug delivery due to their exceptional biocompatibility and responsiveness to physiological microenvironments. However, fabricating microgel formulations based on LMWGs is extremely challenging due to the intrinsic fragility of the self-assembled networks. To mitigate the thermodynamic limitation of LMWGs, we developed an in-droplet self-assembly strategy to fabricate spherical supramolecular microgels. In this approach, mild droplet solidification ensures that ascorbyl palmitate (AP) molecules self-assemble into nanosheets through hydrophobic interactions and hydrogen bonding. As the droplets shrink, these nanosheets concentrate, interpenetrate with each other and form stable microgels. The palmitate-based prodrugs were successfully incorporated into the interdigitated bilayer structure, achieving high drug-loading degree (36.4-47.2 wt%). <i>In vitro</i> and <i>in vivo</i> studies confirmed the inflammation-responsive disassembly of these microgels, leading to flare-dependent, on-demand drug release. While both formulations exhibited comparable therapeutic efficacy in a standard inflammatory arthritis (IA) model, the disease-severity adaptive microgels demonstrated markedly superior therapeutic benefits in a severe IA model compared to non-responsive microspheres designed to resemble clinically utilized formulations. Overall, our results suggest inflammation-responsive supramolecular microgels enabled by controlled in-droplet self-assembly represent a promising next-generation platform for localized drug delivery, with strong potential for clinical translation.