Hydrogel-based senomorphic approaches to modulate cellular senescence and promote tissue rejuvenation.

Abstract

Cellular senescence is a major driver of age-related tissue dysfunction, characterized by chronic inflammation, oxidative stress, mitochondrial impairment, and disrupted extracellular matrix homeostasis. While senolytic strategies that eliminate senescent cells have shown therapeutic promise, irreversible cell loss may be detrimental in tissues with limited regenerative capacity. As a result, increasing attention has shifted toward senomorphic and microenvironment-modulating approaches that attenuate senescent phenotypes while preserving resident cells. However, many senescence-modulating agents are limited by poor solubility, spatial localization and rapid tissue clearance. Hydrogels have emerged as powerful platforms to address these challenges by enabling localized and sustained delivery of senescence-modulating cargos. Beyond serving as passive carriers, hydrogels can be engineered with intrinsic bioactivity and tunable biochemical and physical properties that regulate oxidative stress, inflammatory signaling, and cell-matrix interactions within aged or degenerative tissues. This review summarizes recent advances that demonstrate how hydrogel design can synergistically integrate material-driven rejuvenation with controlled delivery of senomorphic cargos, support multimodal therapeutic strategies, and create defined cellular niches that modulate senescence. Collectively, these developments position hydrogel-based systems as an integrative and versatile framework for spatially precise, mechanism-driven modulation of senescence and age-associated tissue dysfunction.