Synthetic Polymer Based Nano Drug Delivery Systems for Precise Alzheimer’s Disease Therapy

Abstract

Abstract:

Alzheimer’s disease (AD) remains a major global health challenge due to its multifactorial pathology and the limited efficacy of existing therapies, which largely provide symptomatic relief without altering disease progression. A central obstacle to effective treatment is the blood–brain barrier (BBB), which severely restricts the delivery of therapeutics to the central nervous system. In this context, synthetic polymer–based nanoparticles have emerged as versatile platforms capable of improving drug stability, prolonging systemic circulation, and enabling controlled and targeted delivery across the BBB. This review summarizes recent advances in polymeric nanocarriers for AD therapy, with emphasis on translationally relevant systems, including poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(lactic acid)–poly(ethylene glycol) (PLA–PEG), and polyethyleneimine (PEI). We discuss how polymer chemistry, degradation kinetics, and surface functionalization can be rationally engineered to overcome key delivery barriers, while critically addressing inherent trade-offs such as long-term biodegradability and clearance (PCL) and the balance between cytotoxicity and transfection efficiency (PEI). Emerging polymeric architectures, including dendrimers and hybrid systems, are also highlighted for their potential to support multifunctional and tunable delivery strategies. Importantly, we emphasize the increasing role of advanced human-relevant in vitro models—such as brain organoids and BBB-on-a-chip platforms—supported by recent regulatory initiatives promoting New Approach Methodologies (NAMs). These systems provide more predictive tools for evaluating nanoparticle transport, safety, and therapeutic response, thereby strengthening translational confidence. Collectively, this review argues that successful clinical translation of polymer-based nanotherapies for AD will depend on the development of hybrid polymer systems validated in advanced human models, alongside early consideration of manufacturability and regulatory alignment.