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Osteosarcoma remains a highly aggressive bone malignancy with limited therapeutic outcomes due to systemic toxicity and multidrug resistance associated with conventional doxorubicin (DOX) chemotherapy. To address these challenges, this study reports the development of a novel localised drug delivery platform comprising DOX-encapsulated amorphous silica nanoparticles (aSNs) embedded in sodium alginate (SA) and polyvinyl alcohol (PVA) nanocomposite films. aSNs were synthesised via sol–gel methods and characterised for their drug loading efficiency, achieving 95.3 ± 2.01% encapsulation. These nanoparticles were integrated into PVA/SA films to fabricate aSNs@SA + PVA nanocomposite films, followed by comprehensive characterisation using SEM, Fourier transform infra-red spectroscopy, swelling, porosity, thermal analysis, and biodegradation studies. The optimised 10 Wt.% aSNs@SA + PVA nanocomposite film exhibited desirable swelling (85.9%), high porosity (90.28%), and moderate biodegradation (50.99%), supporting its suitability for localised therapeutic applications for bone tissue regeneration. In vitro drug release showed sustained and pH-responsive behaviour, with significantly enhanced DOX release under acidic tumour-mimicking conditions (pH 5.5) compared with physiological pH (7.4). Cell viability assessment using MG-63 cells demonstrated potent cell proliferation efficacy, comparable with tissue culture polystyrene plate control after 24 h. These results indicate that the aSNs@SA + PVA nanocomposite film offers a promising strategy for osteosarcoma treatment and reduced systemic toxicity.

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