Herein, silk fibroin nanoparticles (FNPs) were explored as a potential oral delivery system, with 04 representative oral drugs belonged to different Biopharmaceutics Classification System (BCS) classes, including ascorbic acid (class I), dextromethorphan (class II), paracetamol (class III), and paclitaxel (class IV). The 04 drug-loaded FNP formulas demonstrated spherical nanosized particles of 300–420 nm with dominant silk-II structures, negative zeta potentials of - 17 mV, varied entrapment efficiencies, and physico-chemical stabilities of > 3 months. In the gastrointestinal condition, the particles significantly enhanced the class-II- and class-IV-drug solubility and sustained their release rates to > 72 h. For the BCS class-I- and class-III-drugs, the particles prolonged the drug release to 6 h. Moreover, the FNP could bypass the pH variations in the gastrointestinal tract and increase the drug permeability across the intestinal membrane by facilitating the drug cellular internalizations. Conclusively, the FNP is a versatile
system for the oral delivery of different pharmaceutical agents.