Liang Han

Lysosome-targeting chimeras specifically degrade membrane/extracellular proteins with the specificity and potency highly dependent on the expression pattern and kinetics of lysosome-targeting receptors. Here we describe an endosome-phagophore linking assembly (EPLA), which is constructed by attaching a specific ligand for a protein of interest (POI) to an endosome surface-anchored phagophore-targeting peptide (ES-PTP) that consists of a pH-low insertion peptide and a phagophore-binding element. EPLAs degrade proteins by binding with POIs, being internalized into endosomes, inserting endosome membrane, anchoring the phagophore-targeting moiety onto endosome surface, and then triggering the spatial proximity of endosomes to phagophores. We show the modularity and generality of the EPLA technology by degrading membrane-bound PD-L1, RAGE, GRP94, PSMA, ICAM-1, p32, VCAM-1 and LRP1, and extracellular amyloid-β and tau. Our results establish a technology platform for autophagic degradation of the membrane/extracellular POIs, which may have broad implications for biochemical research and clinical therapeutics.

Blood-brain barrier (BBB) dysfunction is an early pathological hallmark of Alzheimer’s disease (AD), occurring prior to amyloid-β (Aβ) accumulation. A key factor contributing to BBB damage in AD is the loss of endothelial expression of low-density lipoprotein receptor-related protein 1 (LRP1). Endothelial LRP1 is crucial for maintaining BBB integrity and facilitating the transcytosis of Aβ across the BBB for peripheral clearance. However, LRP1 is also expressed in other neural cell types, such as neurons, where it paradoxically promotes Aβ generation and tau propagation. These dual roles of LRP1 for different cell types present a challenge for developing effective AD therapy targeting LRP1. Simvastatin (SIM), an HMG-CoA reductase inhibitor, has been shown to induce compensatory upregulation of LRP1 expression. To harness this potential, we designed SIM-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) that can be effectively internalized by endothelial cells. Our findings demonstrate that intravenous (IV) injection with S@A-NPs upregulates endothelial LRP1 expression level, repairs BBB damage, attenuates Aβ accumulation, mitigates neurodegeneration, and ultimately preserves cognitive function in APP/PS1 mice. These results highlight the potential of endothelial delivery of SIM via nanoparticles to attenuate AD pathogenesis. Our study proposes a novel therapeutic strategy for AD by leveraging nanoparticle-mediated drug delivery.

The Wnt signaling pathway has a significant regulatory part in tissue development and homeostasis. Dysregulation of the Wnt signaling pathway has been associated with many diseases including cancers and various brain diseases, making this signaling pathway a promising therapeutic target for these diseases. In this review, we describe the roles of the Wnt signaling pathway in the blood-brain barrier (BBB) in intracranial tumors and peripheral tumors, from preclinical and clinical perspectives, introduce Wnt-regulated therapeutics including various types of drugs and nanomedicines as BBB modulators for brain-oriented drug delivery and as therapeutic drugs for cancer treatments, and finally discuss limitations and future perspectives for Wnt-regulated therapeutics.

Receptor‐mediated vesicular transport has been extensively developed to penetrate the blood‐brain barrier (BBB) and has emerged as a class of powerful brain‐targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low‐density lipoprotein receptor‐related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein‐coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)‐loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti‐angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94‐positive brain diseases.