Background: Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. Results: In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. Conclusions: TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics. Graphical

Melittin, the principal constituent in bee venom, is an attractive candidate for cancer therapy. However, its clinical applications are limited by hemolysis, nonspecific cytotoxicity, and rapid metabolism. Herein, a novel genetically engineered vesicular antibody‐melittin (VAM) drug delivery platform was proposed and validated for targeted cancer combination therapy. VAM generated from the cellular plasma membrane was bio‐synthetically fabricated, with the recombinant protein (hGC33 scFv‐melittin) being harbored and displayed on the cell membrane. The bioactive and targetable nanomelittin conjugated by hGC33 scFv could be released in an MMP14‐responsive manner at tumor sites, which reduced off‐target toxicity, especially the hemolytic activity of melittin. Importantly, VAM could be loaded with small‐molecule drugs or nanoparticles for combination therapy. Nanomelittin formed pores in membranes and disturbed phospholipid bilayers, which allowed the anticancer agents (i.e., chemotherapeutic drug doxorubicin and sonosensitizer purpurin 18 nanoparticles) co‐delivered by VAM to penetrate deeper tumor sites, leading to synergistic therapeutic effects. In particular, the punching effect generated by sonodynamic therapy further improved the immunomodulatory effect of nanomelittin to activate the immune response. Taken together, our findings indicate that clinically translatable VAM‐based strategies represent a universal, promising approach to multimodal synergetic cancer therapy.

Tau protein aggregation is a defining characteristic of Alzheimer's disease (AD), leading to the formation of neurofibrillary tangles that disrupt neural communication and ultimately result in cognitive decline. Nanotechnology presents novel strategies for both diagnosing and treating Alzheimer's disease. Nanotechnology. It has become a revolutionary tool in the fight against Alzheimer's disease, particularly in addressing the pathological accumulation of tau protein. This review explores the relationship between tau-related neurophysiology and the utilization of nanotechnology for AD treatment, focusing on the application of nanomaterials to regulate tau phosphorylation, hinder tau aggregation and propagation, stabilize microtubules, eliminate pathological tau and emphasize the potential of nanotechnology in developing personalized therapies and monitoring treatment responses in AD patients. This review combines tau-related neurophysiology with nanotechnology to provide new insights for further understanding and treating Alzheimer's disease.

This review summarizes the classifications, advantages, and applications of nanodiscs in disease therapy.