Cordycepin, a major compound of Cordyceps sp., has been shown to have anticancer potential. However, its low solubility in water is a hurdle in drug delivery in the human body and for cellular uptake. This study focuses on the ability to load cordycepin onto a biodegradable silica nanoparticle as an effective nanocarrier. Biodegradable tetrasulfide-based organosilica nanomaterial with homogeneously spherical particles, average particle size of approximately 50 nm, and pore size of 3.56 nm were successfully synthesized. The nanomaterial could efficiently load cordycepin with a loading capacity up to 755.02 mg g−1. The release profile of cordycepin-loaded nanoparticles at pH 5.5 showed a burst release within the first 1 h and a gradually slow rate thereafter. Moreover, the results of in vitro toxicity of the drug-loaded material against two malignant cancer cell lines including gastric (AGS) and lung (A549) indicated the potential of the nanosystem for drug delivery in cancer therapy. Display omitted ➢Biodegradable nanoparticles (NPs) were successfully prepared by sol-gel condensation of ethane- and tetrasulfide-based linkers.➢The synthesized NPs possess a high specific surface area and a large pore size (3.56 nm) with small particle size approximately 50 nm.➢NPs could completely degrade under redox condition after 7 days➢The material showed high loading capacity of cordycepin, up to 755.02 mg g−1.➢In vitro toxicity studies exhibited that cordycepin-loaded NPs could efficiently kill cancer cells (AGS and A549), but not harm the normal cells at moderate concentrations.