Objective: To design a VEGF monoclonal antibody (mAb)-modified nanoparticles co-loaded with paclitaxel (PTX) and etanidazole (ETA) for radioresistance in hypoxic tumor cells. Methods: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles co-loaded PTX and ETA were prepared using a single emulsion-solvent evaporation method. VEGF monoclonal antibodies were conjugated to the nanoparticles via carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling. High-performance liquid chromatography (HPLC) was employed to analyze drug encapsulation efficiency, loading capacity, and drug release simulated in vitro. The morphology of nanoparticles was observed by scanning electron microscopy (SEM). Cellular uptake of nanoparticles by human breast cancer MCF-7 cells and cervical cancer HeLa cells was evaluated using fluorescence microscopy. The effect of drug loaded nanoparticles on the clonal formation ability of tumor cells were analysed and detected by cell survival. Results: The targeted nanoparticles exhibited a spherical morphology with an average particle size of approximately 120 nm. The drug loading capacities for PTX and ETA were 4.66% and 1.94%, respectively. In vitro release profiles demonstrated biphasic characteristics: PTX showed sustained release (30% over 5 days), while ETA exhibited rapid release (50% within 3 h and 90% within 24 h). VEGF antibody modification significantly enhanced nanoparticle uptake by both MCF-7 and HeLa cells. Combined with 10 Gy radiation, the targeted nanoparticles significantly reduced the colony formation rate of hypoxic tumor cells compared to non-targeted counterparts. Conclusion: The developed nano-system synergistically enhanced radiotherapeutic efficacy through dual mechanisms of hypoxia targeting and spatiotemporally differential drug release to provide a novel strategy to overcome tumor radioresistance.