Targeting angiogenesis: advances in the design and engineered applications of nanobodies

Angiogenesis is a fundamental physiological process; however, its pathological dysregulation drives diseases such as solid tumors, wet age-related macular degeneration, and rheumatoid arthritis. Although clinically effective, conventional anti-angiogenic monoclonal antibodies are limited by poor tissue penetration, off-target toxicities, and susceptibility to compensatory resistance. This review systematically examines the structural advantages and engineering strategies of nanobodies (Nbs) targeting angiogenesis-related pathways. Advanced engineering approaches, such as AI-assisted humanization and multivalent assembly, effectively mitigate immunogenicity and extend serum half-life. Furthermore, multispecific designs can simultaneously block compensatory pathways to circumvent resistance. Moreover, preclinical studies indicate that integrating these molecules into site-specific nanobody-drug conjugates and targeted delivery vehicles may improve therapeutic precision and local drug accumulation; however, their long-term safety, manufacturability, and clinical benefit remain to be established. Functionalizing Nbs with radionuclides or fluorophores may enable the development of novel theranostic platforms that support real-time molecular imaging and image-guided surgery. In parallel, nanobody-based CAR-T (Nb-CAR-T) cells facilitate the targeted remodeling of the disease microenvironment. Ultimately, this review highlights the value of engineered Nbs as a highly programmable and transformative platform. By overcoming key limitations of conventional antibodies, engineered nanobodies open new avenues for precise, multi-dimensional interventions in solid tumors. Their potential in certain non-neoplastic angiogenic diseases is emerging but requires further validation.