EZN-3042

Clearly, a growing body of preclinical evidence demonstrates the improved anticancer efficacy of co-delivery for siRNA with chemotherapeutic agents by simultaneous modulation of MDR mechanisms and amplification of cytotoxic responses. Indeed, through siRNA-mediated silencing of the target genes, one might restore chemosensitivity, increase apoptotic signalling, reduce angiogenesis, and suppress epithelial-mesenchymal transition in diverse cancer models of Bcl-2, survivin, VEGF, EGFR, HER2, c-MET, and MUC1. Furthermore, nanocarrier platforms, comprised of lipid nanoparticles, polymeric systems, dendrimers, and mesoporous silica nanoparticles consistently enhance siRNA stability, tumour accumulation, and coordinated release with chemotherapeutic payloads, driving synergistic tumour growth inhibition both in vitro and in vivo. Early clinical candidates, such as EZN-3042 and ALN-VSP, achieved target engagement and biological activity, while limitations included variable tumour uptake, dose-limiting toxicities, and complex pharmacokinetic behaviour. Comparative consideration of the literature suggests that tumour heterogeneity, nanoparticle biodistribution variability, incomplete endosomal escape, and the risk of immune activation are strong modulators of therapeutic performance. These constraints notwithstanding, siRNA-chemotherapy combinations are a highly promising strategy with clear mechanistic rationale and extensive preclinical validation. Translation to clinical practice will depend on optimised delivery platforms, reproducible pharmacokinetic/pharmacodynamic synchronisation, and rigorous evaluation of safety and off-target effects. Overall, current evidence highlights substantial potential for siRNA-drug co-delivery while emphasizing key challenges to overcome in achieving durable clinically meaningful outcomes.