From molecular pathways to nanocarrier design: a translational framework for lipid-based nanoparticles in Alzheimer's disease

Alzheimer's disease, being a complicated neurodegenerative disoder affects cognitive as well as memory functions. Characterised by amyloid-β aggregation, along with tau hyperphosphorylation, and cholinergic dysfunction, this disease is also associated with oxidative stress and neuroinflammation. Conventional clinical interventions, like acetylcholinesterase inhibitors and novel monoclonal antibodies predominantly rely on symptomatic alleviation of symptoms. Nevertheless, these conventional treatments come across considerable constraints, like temporary effectiveness, lesser therapeutic reach due to the blood brain barrier, apart from additional adverse effects. To overcome these delivery obstacles and achieve intracellular targeting, lipid nanoparticles, such as liposomes, solid lipid nanoparticles, and drugs, that can effectively traverse biological barriers, and facilitate precise intracellular release. This review introduces a translational, pathway-integrated framework that connects key molecular mechanisms of the disease with rational design strategies of lipid nanocarriers. The review also illustrates how essential internal factors, such as lipid composition, ionizable lipid pKa, selection of helper lipids, PEG density, along with methods of endosomal escape, and the protein corona, affect brain targeting efficacy and toxicity. It further focuses on pathway-enforced nano lipidic therapeutic approaches, where nanocarrier design is tailored to cater to specific biological targets. Nano lipidic delivery of siRNA, miRNA, mRNA, monoclonal antibodies, and along with other neuroprotective agents has been emphasised. Additionally, advancements in surface functionalization, intranasal administration, as well as receptor-mediated transcytosis, and focused ultrasound-driven blood-brain barrier penetration have also been highlighted in this review. Therefore, it aims to bridge the gap between molecular pathology and formulation design through alignment of design principles that emphasize on nanocarrier properties and its relevance to disease-specific requirements, an approach that has never been comprehensively addressed in previous literature.Registration number of clinical trial: Not applicable.

Abstract from PubMed (PMID 42980730). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.