Stealth Drug Delivery of Mouse Serum Albumin‐Coated Paclitaxel‐Loaded Gelatin Nanoparticles for Targeted Cancer Therapy in Mice

ABSTRACT Nanoparticle (NP)‐based drug delivery faces a major challenge due to rapid clearance by the immune system, primarily through opsonization and phagocytosis. To address this, we developed paclitaxel (PTX)‐loaded gelatin nanoparticles (GNPs) coated with mouse serum albumin (MSA) (MSA@PTX‐loaded GNPs) for localized tumor therapy. Physicochemical characterization confirmed successful MSA coating, leading to an increase in hydrodynamic size (∼120 nm) and a shift in surface charge from −11.50 mV (blank GNPs) to 1.50 mV (MSA@PTX‐loaded GNPs). The MSA coating significantly reduced in vitro protein adsorption (∼4 µg/mL) compared to uncoated GNPs (∼19 µg/mL). Drug release studies demonstrated sustained and pH‐responsive PTX release, with 25% of PTX released within 6 h in an acidic tumor environment, while release remained lower (∼10%) under physiological conditions (pH 7.4). In vivo studies using tumor‐bearing mice demonstrated that subcutaneously administered MSA@PTX‐loaded GNPs significantly enhanced tumor suppression compared to uncoated PTX‐loaded GNPs, while also reducing systemic toxicity. Histopathological analysis revealed reduced immune cell infiltration in the MSA‐coated group. Additionally, in vivo analysis in tumor‐bearing mice treated with MSA@PTX‐loaded GNPs showed significant recovery compared to uncoated PTX‐loaded GNPs and untreated controls. This study presents a promising strategy for improving localized chemotherapy, enhancing therapeutic efficacy, and reducing off‐target effects.