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To circumvent this, poly(lactic-co-glycolic acid) (PLGA)\u2013polyethylene glycol (PEG)\u2013based nanoparticles were developed as a platform for the codelivery of synergistic drug ratios, improving therapeutic efficacy by increasing the percentage of injected dose reaching the tumor. Nonetheless, extravasation-dependent tumor accumulation is susceptible to variations in tumor vasculature; therefore, PLGA-PEG was modified with sulfates to actively target P-selectin\u2013expressing cancers. Here, we show the potential of our platform in unique three-dimensional (3D) in vitro and in vivo models. The P-selectin\u2013targeted nanoparticles showed enhanced accumulation in 3D spheroids and tissues of P-selectin\u2013expressing BRAF-mutated melanomas and BRCA-mutated breast cancers, resulting in superior in vivo efficacy and safety. 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