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Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins

ABSTRACT: Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act as next-generation TPD platforms. However, the molecular mechanism underlying their degradation remains unknown, which restricts their application in TPD. In this study, we found that the autophagy-mediated lysosomal pathway was the major route by which EVs were degraded. MAP1LC3B recognized the LIR motifs of SQSTM1 and induced the degradation of EVs in the autophagy pathway. Based on the EV degradation mode, we developed an EV-based targeted protein degradation platform (EVTPD) using EVs loaded with the LIR motif of SQSTM1 as a degradation signal. Additionally, target protein-binding domains were integrated into the EVTPD to capture target proteins. EVTPD selectively degraded extracellular proteins without requiring receptors on target cells. Furthermore, dual-targeting EVTPD effectively degraded both TNF-α and IL-1β and exhibited potent anti-inflammatory effects in a rat and goat models of intervertebral disc degeneration. This study has established a modular EV-based TPD strategy with multi-targeting potential.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312760 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab aggregates in the brain of APP/PS1 mice An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

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Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins

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