Oxidative Stress and Lysosomal Dysfunction in Neurodegenerative Diseases: Underlying Mechanisms and Nanotherapeutic Targeting Strategies

Abstract

Neurodegenerative diseases (NDDs), defined by the progressive loss of neurons, present a major challenge to global health. Oxidative stress and lysosomal dysfunction are both key pathogenic factors in NDDs, and they do not operate in isolation; instead, the vicious cycle they form, often mediated through organellar crosstalk, serves as the core driver of the pathological progression of NDDs, collectively worsening disease outcomes. Specifically, excessive reactive oxygen species (ROS) can disrupt lysosomal membrane integrity through lipid peroxidation and inhibit the activity of vacuolar ATPase (V-ATPase), ultimately leading to impaired lysosomal acidification. Meanwhile, lysosomal dysfunction hinders the clearance of damaged mitochondria (the primary endogenous source of ROS), toxic protein aggregates, and free iron ions. This further exacerbates ROS accumulation and accelerates neuronal degeneration. Conventional therapeutic approaches have limited efficacy, primarily due to the challenges in crossing the blood–brain barrier (BBB), insufficient targeting ability, and an inability to effectively intervene in this pathological loop. Nanotherapeutics, leveraging their tunable physicochemical properties and modular functional design, represent a transformative strategy to address these limitations. This review systematically elaborates on the reciprocal interplay between oxidative stress and lysosomal dysfunction in NDDs, with a particular focus on the central role of lysosome-mitochondria axis dysfunction, critically appraises recent advances in nanotechnology-based targeted therapies, and thereby provides a comprehensive theoretical framework to guide the development of novel NDD therapeutics.