pH-Responsive Supramolecular Nanoscale Micelles for Targeted Dexamethasone Delivery and Senescence Modulation

Cellular senescence, an irreversible state of cell-cycle arrest accompanied by the pro-inflammatory senescence-associated secretory phenotype (SASP), is a key driver of aging and disease, underscoring the critical need for therapeutic modulation. We engineered a pH-responsive supramolecular nanoscale micelle (SNM, ∼69 nm) based on host–guest chemistry for targeted delivery of dexamethasone (DEX) for modulation of DNA damage response (DDR), a key mechanism stabilizing the senescence state. DEX-loaded SNM (DEX-SNM, ∼105 nm) exploits the high number of acidic lysosomes (pH 4.5), a characteristic feature of senescent cells, to achieve a selective intracellular drug release. In vitro studies demonstrated that DEX-SNMs successfully modulated the DDR pathway, evidenced by the reduction in key senescence markers: γH2AX (decreasing from 2.164- to 1.535-fold change) and p16INK4a (decreasing from 1.851- to 1.381-fold change), which demonstrated superior efficacy over free DEX. Furthermore, the treatments attenuated senescence evidenced by cell-cycle modulation and a substantial reduction in apoptosis. This work establishes a potent, pH-responsive micellar system as an effective nanomaterial for targeted drug delivery to senescent cells and subsequent therapeutic senomodulation.