Cholinergic Neuron Targeting Nanosystem Delivering Hybrid Peptide for Combinatorial Mitochondrial Therapy in Alzheimer’s Disease

Abstract

Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer's disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic therapeutic effects. Therefore, we developed a multifunctional hybrid peptide HNSS composed of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin. However, suitable peptide delivery systems with excellent loading capacity and effective at-site delivery are still absent. Herein, the nanoparticles made of citraconylationmodified poly(ethylene glycol)-poly(trimethylene carbonate) polymer (PEG-PTMC(Cit)) exhibited desirable loading of HNSS peptide through electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1(FGFR1) overexpression in both the blood−brain barrier and cholinergic neuron, an FGFR1 ligand-FGL peptide was modified on the nanosystem (FGL-NP(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation in brain with preferred distribution into cholinergic neurons in the diseased region. The acid-sensitive property of the nanosystem facilitated lysosomal escape and intracellular drug release by charge switching, resulting in HNSS enrichment in mitochondria through directing of the SS31 part. FGL-NP(Cit)/HNSS effectively rescued mitochondria dysfunction via the PGC-1α and STAT3 pathways, inhibited Aβ deposition and tau hyperphosphorylation, and ameliorated memory defects and cholinergic neuronal damage in 3xTg-AD mice. The work provides a potential platform for targeted cationic peptide delivery, harboring utility for peptide therapy in other neurodegenerative diseases.

A Mitochondrial Perspective on Noncommunicable Diseases

“…Mitochondria-targeting nanocomposites gold-selenium core-shell nanostructures (AS-I/S NCs) modified with the antioxidant peptide SS31 can achieve mitochondria-targeted ROS inhibition [ 84 ]. The multifunctional heterogeneous peptide HNSS consisting of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin piggybacked on PEG-PTMC (Cit) nanoparticles enriched in mitochondria can effectively improve mitochondrial dysfunction by alleviating oxidative stress and restoring mitochondrial ultrastructure [ 85 ].…”

Construction of a DNA Nanoassembly Based on Spatially Ordered Recognition Elements for Inhibiting β-Amyloid Aggregation

“…The new strategy made it possible by an improved understanding of the assembly mechanism of Aβ at the molecular level, which will continue to guide rational therapeutic agents against AD. , The Aβ aggregation process is a spontaneous process in which an Aβ monomer transforms from its initial structure into an oligomer, then assembles to form pro-fibril, and finally aggregates into mature fibril under certain conditions. , The slow self-aggregation in the lag phase and fibril-catalyzed secondary nucleation in the elongation phases are a high orderly assembly process. Conformationally, the original random coil or helical structure changes into a regularly arranged β-sheet structure.…”

Endogenous miRNA and K+ Co-Activated Dynamic Assembly of DNA Coacervates for Intracellular miRNA Imaging and Mitochondrial Intervention

“…Mitochondria are subcellular organelles with two layers of membrane and serve as the energy supply station of the cell. − Rational regulation of organelles, is a useful strategy to control the behavior and fate of cells. , Mitochondrial dysfunction can affect the normal function of cells, leading to a series of diseases including cancer. − Therefore, mitochondria have become the target of many therapeutic drugs in recent years. The dynamic construction of artificial architecture in living cells guided by mitochondrial-targeting molecules is a promising method for mitochondrial intervention.…”

“…28−31 Rational regulation of organelles, is a useful strategy to control the behavior and fate of cells. 32,33 Mitochondrial dysfunction can affect the normal function of cells, leading to a series of diseases including cancer. 34−36 Therefore, mitochondria have become the target of many therapeutic drugs in recent years.…”