Targeting tumor angiogenesis: advances in VEGF-A siRNA-loaded nanocarriers for anti-angiogenic cancer therapy

Angiogenesis is a fundamental hallmark of solid tumor progression, with vascular endothelial growth factor-A (VEGF-A) serving as a central regulator of tumor vascularization, immune suppression, and therapeutic resistance. Although monoclonal antibodies and tyrosine kinase inhibitors targeting VEGF have demonstrated clinical benefit, their efficacy is frequently limited by adaptive resistance, systemic toxicity, and incomplete suppression of VEGF signaling. Small interfering RNA (siRNA)-mediated silencing of vascular endothelial growth factor-A (VEGF-A), the predominant pro-angiogenic isoform in cancer, offers a gene-specific strategy capable of inhibiting angiogenesis at the mRNA level; however, its clinical translation is constrained by rapid nuclease degradation, poor cellular uptake, and endosomal entrapment. This review critically examines nanocarrier-based delivery systems developed for VEGF-A-targeted siRNA (siVEGF-A), including lipid nanoparticles, polymeric and dendrimer-based carriers, inorganic platforms, biomimetic systems, and hybrid nanostructures. Across multiple preclinical cancer models, these systems consistently achieve substantial VEGF knockdown (typically 60-80%), leading to marked reductions in tumor microvessel density and significant tumor growth inhibition. Co-delivery strategies integrating siVEGF-A with chemotherapeutic agents such as doxorubicin or irinotecan further enhance antitumor efficacy by synergistically suppressing angiogenesis while sensitizing tumours to cytotoxic therapy. Despite encouraging preclinical outcomes, challenges related to formulation stability, biodistribution, immune activation, endosomal escape efficiency, and scalable manufacturing remain major barriers to clinical translation. By synthesizing mechanistic insights, therapeutic outcomes, and translational limitations, this review highlights key design principles and future directions for the development and clinical translation of VEGF-A siRNA-loaded nanocarriers for anti-angiogenic cancer therapy.