Tunable microgel modulars for temporally coordinated combination therapy.

Hydrogels are widely used in local drug delivery, however, achieving independent and programmable release of multiple drugs from a single formulation remains a major challenge, particularly for combination therapies requiring precise temporal coordination. Inspired by the customizable assembly of LEGO bricks, we developed an injectable modular microgel platform for programmable multi-drug delivery by combining distinct microsphere modules-each optimized for specific drug types. For example, Gelatin methacrylate microspheres for hydrophilic drugs and Alginate microspheres for hydrophobic drugs. The resulting composite microgel exhibits outstanding injectability, rapid self-healing properties, and prolonged in vivo retention, ensuring stable and sustained drug delivery. By modulating matrix concentrations, we achieved precise tuning of release profiles across a broad spectrum of therapeutic agents, from small molecules to large proteins. We demonstrated clinical potential in two applications: (1) Sequential delivery of carboplatin followed by RSL3 overcame chemotherapy resistance, extending mouse survival by 10 days compared to conventional hydrogels. (2) Controlled release of doxorubicin and paclitaxel leveraged their distinct mechanisms to eliminate cancer cells, reducing tumor mass 3.53-fold versus traditional hydrogels. This modular microgel strategy transcends the limitations of conventional monolithic systems by enabling the independent programming of drug release profiles, offering a versatile and customizable platform for implementing sophisticated temporal combination therapies with enhanced precision and therapeutic outcomes.