Engineering nanobodies for drug delivery systems in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) remains a major global health challenge, with current therapies offering only symptomatic relief. A significant constraint in the development of effective treatments is the blood-brain barrier (BBB), as it greatly limits the access of therapeutic drugs targeting amyloid-β (Aβ) aggregation, tau hyperphosphorylation and neuroinflammation. Nanobodies, single-domain antibody fragments derived from camelids, have emerged as versatile tools with unique properties such as small size, high stability and the ability to penetrate the BBB. Engineered formats allow for specific targeting of Aβ and tau, receptor-mediated transcytosis, and conjugation with therapeutic or diagnostic substances. Preclinical studies show that nanobody-based strategies can reduce pathological burden, attenuate neuroinflammation and improve cognitive outcomes in AD models. Manufacturing scale-up, long-term safety and regulatory validation are among the remaining challenges, yet nanobody engineering represents a viable path to disease-modifying medicines. Innovative approaches, including artificial intelligence-driven design, i.e. 4-1BB agonist nanobodies, and clustered regularly interspaced short palindromic repeat-facilitated diversification of nanobody libraries - such as targeted complementarity-determining region 3 mutagenesis followed by functional screening against disease-relevant tau or Aβ conformers - alongside half-life extension strategies, are commencing to surmount these obstacles and enhance the potential of nanobody platforms to develop into clinically viable disease-modifying therapies.