CD44-targeted nanoparticles for remodeling the tumor microenvironment in a 3D macrophage-embedded ovarian cancer model with stem cell-like features.

Ovarian cancer frequently develops resistance to chemotherapy, which is driven by cancer stem cells (CSCs) and an immunosuppressive tumor microenvironment (TME) shaped by tumor-associated macrophages (TAMs). This study explored the therapeutic potential of CD44-targeted, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CD44-PLGA-DTX NPs) in overcoming chemoresistance in ovarian cancer. A 3D spheroidal model incorporating SKOV3 ovarian cancer cells and TAMs was developed to mimic the TME for in vitro investigations. CD44-PLGA-DTX NPs exhibited significantly enhanced cellular uptake within the macrophage-embedded SKOV3 spheroids, which resulted in reduced cell viability and a reversal of chemoresistance. Cytokine profiling further revealed that the NPs promoted TAM polarization from the protumor M2 phenotype to the antitumor M1 phenotype, thus fostering an antitumor immune environment. These findings highlight the potential of CD44-targeted NPs as a dual-targeted therapeutic strategy, targeting both CSCs-driven tumor growth and TME reprogramming, thereby improving ovarian cancer treatment outcomes.