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Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a β-sheet breaker acting on Aβ, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aβ, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aβ and p-tau, confirming the promising application of nano-combination strategy in AD treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

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 citraconylation-modified 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.

Intervention of the over-activated microglia-aggravated neuroinflammation represents a promising therapeutic strategy for Alzheimer's disease (AD). Upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) attenuates the neuroinflammatory processes and normalizes the dysfunctional microglia. However, Trem2-gene therapy for AD by the effective non-invasive delivery systems is unexploited. Herein, we report the microglia-targeted gene delivery systems (PHSA@PF/pTREM2) composed of a core of fluorinated polyethylenimine condensing the TREM2-encoding plasmid (PF/pTREM2) and a shell of human serum albumin conjugated with both cis-aconitic anhydride and neural cell adhesion molecule-mimetic peptide P2 (PHSA). Thanks to the shedding effect of the albumin coated, PHSA@PF/pTREM2 exhibit prolonged blood circulation and low cytotoxicity. PHSA@PF/pTREM2 achieve brain accumulation as high as 2.17% injected dose per gram of brain and the microglial-targeting effect (targeting specificity of 41.9%) via the systemic administration. The nanocomplexes can be detached PHSA-shell in the acidic endo-lysosomes via the cleavage of cis-aconitic amide bond, resulting in PF/pTREM2 exposure for efficient endo-lysosomal escape and gene transfection. PHSA@PF/pTREM2 upregulate the TREM2 level and regulate microglial polarization toward M2-phenotype for remodeling the inflammatory microenvironment and enhanced Aβ clearance, leading to an improvement of cognitive performance in APP/PS1 mice. This work provides a promising gene delivery platform to reverse dysfunctional microglia for AD therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mitochondrial dysfunction is an early event of Alzheimer's disease (AD), contributes the onset and progression of AD, and may represent an effective therapeutic target for AD intervention. Since mitochondria in central neurons are more susceptible to oxidative damage than non-neuronal cells, the specific delivery of the antioxidants to the mitochondria of impaired central neurons is crucial for achieving the therapeutic effect on AD. Here, we prepare the neuronal mitochondria-targeted micelles (CT-NM) through co-decoration with neural cell adhesion molecule (NCAM) mimetic peptide C3 for brain neuron specific binding and the triphenylphosphonium (TPP) for mitochondrial targeting. CT-NM significantly increase the encapsulated resveratrol's concentration in the neuronal mitochondria compared to the micelles modified with C3 only or the resveratrol solution. The resveratrol-loaded CT-NM alleviate the oxidative stress in the neuronal cells, resulting in stabilization of the dynamic balance of mitochondrial fission and fusion. The targeted micelles restore the cognitive performance in APP/PS1 transgenic mice to the level of wild-type mice characterized by up-regulation of sirtuin 1 expression, reduction of amyloid deposition and tau hyperphosphorylation, protection of synapses and inhibition of microglia proliferation. The results demonstrate the delay of the progression of AD through reversing neuronal mitochondrial dysfunction by the targeted delivery of antioxidants., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)