Targeting Cellular Senescence and the Extracellular Matrix for Tissue Regeneration: Mechanistic Evidence and a Proposed Therapeutic Framework

Persistent cellular senescence and extracellular matrix (ECM) dysfunction can impair tissue repair, whereas some transient senescence-associated states support healing. This critical narrative review distinguishes evidence for senescent-cell clearance, modulation of senescence-associated phenotypes, and functional tissue repair. A citation-led reassessment supplemented by a targeted literature update was used to examine mechanistic, biomaterial, and clinical evidence; the review was not systematic. Senolytics exhibit cell-type-dependent activity in preclinical models, while ECM-derived materials can support adhesion, survival, and differentiation without demonstrating senolysis. FOXO4–p53-directed peptides, fibronectin modules, and responsive carriers raise unresolved questions regarding target specificity, stereochemistry, intracellular delivery, and potentially antagonistic survival signaling. The studies reviewed do not establish that combining senolysis with ECM-mediated instruction yields superior in vivo regeneration compared with either component treatment alone. We therefore present this integration as a testable hypothesis and propose a two-phase framework, informed by cell-resolved assessment, that preserves acute physiological repair before considering delayed clearance of persistent harmful cell populations. Early human trials provide evidence regarding feasibility, tissue markers, circulating biomarkers, and exploratory functional outcomes, but do not establish regenerative efficacy. Clinical translation requires comparative combination studies, formulation-specific pharmacological and safety assessments, and durable restoration of tissue structure and function.