LAbs@Lip@BMn/Rapa demonstrates efficient blood-brain barrier penetration and enhances cognitive functions in Alzheimer's disease model mice.
Neuroinflammation is linked to microglial overactivation and oxidative stress in Alzheimer's disease.
Engineered apoptotic bodies derived from brain metastatic tumor cells are developed to mitigate chronic neuroinflammation.
The LAbs@Lip@BMn/Rapa nanocomposite shows effective delivery of therapeutic agents within the Alzheimer's disease microenvironment.
This multi-target strategy normalizes microglia towards an anti-inflammatory state and reduces reactive oxidative species.
The approach promotes clearance of β-amyloid and phosphorylated tau, potentially restoring the pathological brain environment.
Simplified
Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to HOtriggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species () accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment. 2 2
Key numbers
20.4×
Increase in CD206 Expression
Compared to M1 microglia treated with .
5.0×
Decrease in CD86 Expression
Measured after treatment with .
84.83% ± 4.67%
Cell Viability Improvement
Compared to 47.47% viability in untreated cells.
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Declarations. Ethics approval and consent to participate: The protocol for animal experiments was approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University and had received approval from the Animal Investigation Ethics Committee of Xuzhou Medical University (SYXK 2020–0048). Competing interests: The authors declare no competing interests.
