Engineered nanoparticle systems targeting tumor angiogenesis: bridging molecular mechanisms and therapeutic innovations.

Angiogenesis, the formation of new blood vessels from existing vasculature, is a fundamental biological process that becomes dysregulated during tumor progression. In solid tumors, uncontrolled angiogenesis supplies oxygen and nutrients, facilitating growth, invasion, and metastasis. Although anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and related pathways have shown clinical promise, their long-term efficacy is often limited by tumor resistance, hypoxia-induced adaptation, and compensatory signaling mechanisms. Understanding the molecular and cellular basis of tumor angiogenesis is therefore critical for developing more effective therapeutic interventions. This review presents an integrated overview of the key regulators of angiogenesis, including hypoxia-inducible factors, VEGF, fibroblast growth factors, platelet-derived growth factors, and matrix metalloproteinases. Additionally, it discusses alternative vascularization mechanisms such as vasculogenesis, vessel co-option, and vasculogenic mimicry that enable tumors to escape anti-angiogenic blockade. The limitations of current therapeutic approaches are analyzed, with an emphasis on TME resistance, systemic toxicity, and the lack of predictive biomarkers. Furthermore, the review highlights the emerging role of nanotechnology in overcoming these challenges. Engineered nanoparticles including polymeric, lipid-based, metallic, and nucleic acid-based systems offer enhanced stability, targeted delivery, and controlled drug release, improving anti-angiogenic efficacy while minimizing systemic side effects. By integrating molecular understanding with nanoscale engineering, these strategies represent a transformative direction in cancer therapy. Overall, this review underscores the need for multi-targeted, nanotechnology-assisted anti-angiogenic approaches to achieve durable tumor control and improved clinical outcomes.