Angiogenesis is a central hallmark of solid tumor progression, driven largely by vascular endothelial growth factor‑A (VEGF‑A). VEGF‑A regulates tumor vascularization and contributes to immune suppression and resistance to conventional therapies. By promoting new vessel formation, VEGF‑A supports nutrient and oxygen delivery to the tumor microenvironment and facilitates malignant growth and metastasis.
Clinical VEGF inhibitors—such as monoclonal antibodies and tyrosine kinase inhibitors—have produced measurable benefits in some cancers. However, their efficacy is often curtailed by adaptive resistance mechanisms within tumors, systemic toxicities associated with broad VEGF pathway inhibition, and incomplete suppression of VEGF signaling. These limitations motivate exploration of alternative, more specific approaches that can reduce off‑target effects and overcome resistance.
Small interfering RNA targeting VEGF‑A (siVEGF‑A) offers a gene‑specific strategy to inhibit angiogenesis at the mRNA level. By preventing translation of the predominant pro‑angiogenic isoform, siVEGF‑A can directly reduce VEGF‑A production within tumors. Despite its specificity, clinical translation of siRNA therapeutics is hampered by biological barriers: rapid degradation by nucleases in biological fluids, poor intrinsic cellular uptake, and sequestration within endosomal compartments after internalization. Effective delivery systems are therefore essential for siVEGF‑A to reach cytosolic RNAi machinery and mediate robust knockdown.
To address delivery challenges, a diverse set of nanocarrier platforms has been developed for siVEGF‑A. The review categorizes these into lipid nanoparticles, polymeric and dendrimer‑based carriers, inorganic platforms, biomimetic systems, and various hybrid nanostructures. Each class offers distinct advantages and tradeoffs: lipid systems tend to support efficient membrane fusion and cytosolic release, polymeric carriers can be engineered for tunable release and stability, dendrimers provide defined multivalency, while inorganic and hybrid platforms can impart structural robustness or imaging functionality. Biomimetic carriers aim to leverage endogenous components to reduce immunogenicity and improve biodistribution.
Across multiple preclinical cancer models, siVEGF‑A nanocarriers consistently achieve substantial VEGF knockdown, commonly reported in the range of 60–80%. This molecular suppression translates to meaningful biological and therapeutic effects: marked reductions in tumor microvessel density and significant inhibition of tumor growth. These consistent preclinical outcomes indicate that efficient delivery of siVEGF‑A can disrupt angiogenic signaling sufficiently to impair tumor vasculature and restrict tumor progression.
Combining siVEGF‑A with cytotoxic agents is a frequently explored strategy to enhance antitumor efficacy. Co‑delivery formulations reported in the literature include pairing siVEGF‑A with chemotherapeutics such as doxorubicin or irinotecan. These combination approaches aim to simultaneously suppress angiogenesis and sensitize tumor cells to chemotherapy, producing synergistic reductions in tumor burden in preclinical models. Co‑delivery can also enable spatiotemporal coordination of anti‑angiogenic and cytotoxic mechanisms within the tumor microenvironment.
Despite promising preclinical data, several translational barriers persist. Formulation stability during storage and in circulation affects dose reliability. Achieving favorable biodistribution and selective tumor accumulation remains difficult, as off‑target uptake can reduce efficacy and raise safety concerns. Immune activation by delivery vehicles or siRNA can limit tolerability. Efficient endosomal escape is critical for cytosolic engagement of RNAi pathways but is often inefficient. Finally, scalable and reproducible manufacturing of complex nanocarriers is a major challenge for clinical translation.
The review synthesizes mechanistic insights and therapeutic outcomes to identify key design principles for advancing siVEGF‑A nanomedicines. Priorities include optimizing carrier platforms for serum stability and targeted biodistribution, engineering robust endosomal escape mechanisms, minimizing immunogenic components, and developing manufacturable formulations. Co‑delivery strategies that combine gene silencing with chemotherapy may offer synergistic benefits and merit further translational study. The review underscores that, while preclinical results are encouraging, overcoming the practical barriers of safety, delivery efficiency, and production scalability is essential before VEGF‑A siRNA‑loaded nanocarriers can progress to clinical use.