Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment

Alzheimer's disease (AD), characterized by amyloid (A β ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular A β . Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3 β (GSK-3 β ) inhibitor 7-bromoindirubin-3ʹ-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood–brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3 β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.