Injectable Senolytic\nHydrogel Depot for the Clearance\nof Senescent Cells

Small molecules are frontline therapeutics for many diseases;\nhowever,\nthey are often limited by their poor solubility. Therefore, hydrophobic\nsmall molecules are often encapsulated or prepared as pure drug nanoparticles.\nNavitoclax, used to eliminate senescent cells, is one such small molecule\nthat faces challenges in translation due to its hydrophobicity and\ntoxic side effects. Further, as senescent cells exhibit context-dependent\npathologic or beneficial properties, it is preferable to eliminate\nsenescent cells locally. To formulate navitoclax and enable local\ntreatment, we designed an injectable hydrogel loaded with navitoclax\nnanoparticles as a senolytic delivery vehicle. Navitoclax nanoparticles\n(Ø ∼ 110 nm) were prepared via solvent–antisolvent\nnanoprecipitation and formulated in an injectable polymer–nanoparticle\n(PNP) hydrogel to create a local senolytic depot. Navitoclax-loaded\nPNP hydrogels selectively cleared senescent cells in vitro in senescent\nendothelial monolayers. This work demonstrates the value of formulating\nlipophilic small molecules and the potential of localized drug delivery\nstrategies to improve senolytic therapies.