<![CDATA[Background: Cancer remains a leading global health burden, with nearly 20 million new cases recorded in 2022. Chemotherapy, while central to treatment, is limited by systemic toxicity, poor tumor selectivity, and multidrug resistance, compromising both survival and quality of life. Objective: This systematic review evaluates the extent to which gold nanoparticle-based drug delivery systems (AuNP-DDS) reduce chemotherapy-associated side effects while enhancing tumor-selective delivery, by examining their underlying mechanisms, preclinical and clinical efficacy, and safety profiles. Methods: A systematic literature search was conducted following PRISMA 2020 guidelines across PubMed, Scopus, ScienceDirect, and Google Scholar for articles published between 2020 and 2025. Ten studies comprising clinical trials, in vitro, and in vivo models met eligibility criteria and were qualitatively synthesized. Results: Across the included evidence, AuNP-DDS consistently demonstrated reduced systemic toxicity and enhanced tumor-selective accumulation through combined passive (EPR-driven) and active (ligand-based) targeting. Benefits were documented for doxorubicin, gemcitabine, cisplatin, and siRNA-based constructs. No dose-limiting toxicities emerged from reviewed clinical studies, and stimuli-responsive formulations further curtailed off-target drug exposure. Conclusion: AuNP-DDS demonstrate considerable promise for limiting chemotherapy-induced harm through targeted delivery and controlled drug release. However, additional clinical validation and standardized production methods remain essential before widespread clinical adoption.]]>
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