Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.

Extracellular amyloid plaques from Aβ accumulation and intracellular neurofibrillary tangles (NFTs) from hyperphosphorylated Tau (p-Tau), both leading to neuronal dysfunction, synapse loss, and cognitive decline. Nonetheless, achieving an effective therapeutic outcome is challenging due to the limited drug bioavailability through the blood-brain barrier (BBB) and the complex microenvironment within the brain. This study proposes MM-TA for the synergistic treatment of AD, utilizing mesoporous manganese (MM) as a nanocarrier to deliver a LK7 (Aβ-inhibiting peptide) and a DAA (amino acid-peptide) that inhibits Tau-related fibrils formation. A biomimetic nanocarrier (MM-LD@4CM termed as MLDC) encapsulated with 4T1 cell membranes (4CM) was developed, inspired by 4T1 cells' ability to facilitate BBB penetration. Following traversal of the BBB, MLDC concurrently prevented Tau phosphorylation and suppressed Aβ aggregation. Furthermore, by leveraging MM's catalase-mimetic properties, MLDC mitigated oxidative stress and altered the microenvironment associated with AD progression. In contrast to the singular therapeutic agent, MLDC ameliorated nerve damage and enhanced cognitive function in AD mice by reducing Aβ oligomers, phosphorylated Tau, and inflammation, thereby providing a synergistic therapeutic approach with significant potential for effective AD treatment.