Multifunctional biomaterial nanocarriers for gene-chemotherapeutic co-delivery: molecular mechanisms, design strategies and clinical translation in precision cancer therapy

The integration of gene therapeutics with chemotherapeutic agents using multifunctional nanocarrier platforms has emerged as a powerful strategy to overcome the inherent limitations of conventional cancer therapies. Tumor heterogeneity, genetic instability, multidrug resistance and systemic toxicity continue to limit the long-term efficacy of standalone chemotherapy or gene therapy. Multifunctional nanocarriers offer a rational solution by enabling the synchronized, targeted and stimuli-responsive co-delivery of nucleic acids and cytotoxic drugs within a single nanoscale system. These platforms are engineered to protect labile gene payloads, enhance cellular uptake, facilitate endosomal escape and achieve spatiotemporally controlled intracellular release in response to tumor-specific biochemical cues. Such coordinated delivery allows genetic modulation of oncogenic, resistance or survival pathways to sensitize cancer cells to chemotherapeutic-induced damage, thereby amplifying therapeutic synergy while minimizing off-target toxicity. This review comprehensively examines the molecular design principles, intracellular mechanisms, cellular interactions, disease-specific applications and translational challenges associated with multifunctional nanocarrier-based gene-drug co-delivery systems. Emerging trends, including smart programmable nanocarriers, advanced gene-editing payloads and data-driven design approaches are also discussed. These insights highlight the transformative potential of multifunctional nanocarriers to redefine combination cancer therapy and advance precision drug delivery toward clinical translation.