Nanoparticle-based senolytic and senomorphic therapies for healthy aging: design principles, translational evidence, and challenges.

Cellular senescence contributes to age-associated tissue dysfunction through persistent growth arrest, metabolic remodeling, and altered communication with immune and stromal cells. Senolytic therapies preferentially eliminate susceptible senescent cells, while senomorphic therapies modulate harmful senescence-associated activities. Nanoparticle engineering can improve the delivery of these agents through cargo protection, surface functionalization, and controlled release. Surface ligands can promote cellular uptake, and components responsive to lysosomal β-galactosidase, acidic pH, reactive oxygen species, or protease activity can regulate cargo release. The selectivity of these mechanisms depends on biological features that vary among senescent populations and also occur in other cellular states. This review examines how material composition and physicochemical properties influence target recognition, intracellular transport, therapeutic activity, and safety. Representative platforms are evaluated across fibrotic, musculoskeletal, metabolic, oncologic, and neurodegenerative disease models, with particular attention to mitochondrial delivery, immune-mediated clearance, nucleic-acid modulation, and microbiome interactions. Preclinical findings are considered alongside human senotherapy studies, which have primarily evaluated small-molecule drug regimens and yielded preliminary or mixed outcomes. Clinical development requires reproducible manufacturing, pharmacokinetic characterization of both carrier and cargo, and assessment of immunotoxicity and delayed organ injury in older hosts. Progress depends on matching a defined pathological cell population to an appropriate delivery strategy and demonstrating an advantage in therapeutic index or sustained functional outcomes against relevant comparators, including clinically feasible non-nanoparticle treatments where available.