Harnessing Lessons from Gel-Based and Advanced Biomaterial Therapeutics to Enable Direct Cellular Reprogramming.

Direct cellular reprogramming, the conversion of one somatic cell type into another, represents a remarkable advancement in regenerative medicine. Its potential to transform fibrotic tissue into functional parenchyma underscores its therapeutic promise. However, several critical challenges remain unresolved, including limited reprogramming efficiency, the long-term functional stability of converted cells, their integration within pre-existing cellular circuits, and safety concerns related to transgene integration and immunological responses to reprogramming-based viral vectors. Approaches based on the exogenous administration of recombinant proteins and miRNAs have also emerged, though these rely on factors that are naturally prone to exhaustion and degradation, potentially restricting their efficacy. This review is divided into three main sections. The first part addresses direct cellular reprogramming in the context of other cell-based applications, outlining its main applications and current biological limitations. The second part examines how different biomaterials, ranging from hydrogel scaffolds to nanoparticles, can modulate direct cellular reprogramming by providing mechanical and topographical cues and by enabling tighter control over the concentration and spatiotemporal dynamics of reprogramming factors and viral vectors. The third part discusses key findings in biomaterial-assisted reprogramming strategies, highlighting emerging opportunities for clinically translatable approaches. The convergence of regenerative biology and biomaterials science may ultimately generate advanced gel-based and hybrid cellular reprogramming platforms for in vitro testing and, in situ applications, for promoting cell fate stabilization and facilitating the regeneration of damaged tissues and organs.