BACKGROUND Vitexin, a flavonoid in various foods and medicinal plants, has potential clinical, therapeutic and food applications due to its bioactive properties and beneficial health effects. However, its poor water solubility causes low oral bioavailability and poor absorption in the gastrointestinal tract, limiting its practical applications. Encapsulation is an efficient approach to overcome these limitations. This study demonstrates the encapsulation of vitexin into poly(ethylene glycol) methyl ether-grafted chitosan (mPEG-g-CTS)/alginate (ALG) polyelectrolyte complex nanoparticles. RESULTS The vitexin-loaded mPEG-g-CTS/ALG nanoparticles were characterized by Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy and X-ray diffraction. The vitexin-loaded mPEG-g-CTS/ALG nanoparticles had a spherical shape, 50-200 nm in diameter, and negatively charged surface (-27 to -38 mV). They possessed a loading capacity of 4-60%, encapsulation efficiency of 50-100% and antioxidant activity (30-52% 2,2-diphenyl-1-picrylhydrazyl decoloration) when their initial vitexin content was 0.02-0.64 g g-1 polymers. Successful vitexin loading into mPEG-g-CTS/ALG nanoparticles was also indirectly confirmed by the enhanced thermal stability of both polymers and the residual soybean oil used in the emulsion preparation step and delayed oxidative degradation of the residual soybean oil. Vitexin's in vitro release from the mPEG-g-CTS/ALG nanoparticles was very fast in phosphate buffer at pH 11, followed by pH 7, and very slow in acetate buffer at pH 3. The gastrointestinal digestion of vitexin increased by encapsulating into mPEG-g-CTS/ALG nanoparticles. CONCLUSIONS Vitexin-loaded mPEG-g-CTS/ALG nanoparticles were successfully fabricated using a two-step process of oil-in-water emulsion and ionic gelation without the use of pungent odor acids and other crosslinkers. The obtained nanoparticles are suitable for oral intestinal-specific delivery systems. © 2023 Society of Chemical Industry.