Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

Objective:To analyze the clinical presentation, potential pathogenesis, diagnosis, management and prognosis of dural arteriovenous fistula (DAVF) manifesting as bithalamic lesions.Methods:The clinical data of three patients with DAVF manifesting as bithalamic lesions from the First Affiliated Hospital of Xi'an Jiaotong University between August 2019 and August 2020 were analyzed retrospectively, and related literatures were reviewed.Results:Patient 1, a 56-year-old female, presented with a one-month aggressive clinical course of weakness, somnolence, nausea, vomiting, urine incontinence and sitting instability. Patient 2, a 53-year-old male, presented with a one-month aggressive clinical course of disturbance of consciousness, walking with difficulty and decreased higher cortex function. Patient 3, a 68-year-old male, presented with an eight-day aggressive clinical course of memory loss, disturbance of consciousness and mental symptoms. In these three patients, cranial computed tomography (CT) scans showed bilateral hypodensity shadow in thalamus while magnetic resonance imaging (MRI) demonstrated bithalamic edema. Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) presented venous or venous sinus closely related with arteries. Digital substraction angiography (DSA) of the patient 1 demonstrated bilateral occipital artery-straight sinus DAVF treated with surgical excision. Four months later, the patient was consciousness with modified Rankin scale (mRS) score of 5. DSA of the patient 2 demonstrated DAVF supplied by the right external carotid artery and the symptoms were relieved after endovascular embolization. One year after operation, there was no recurrence and mRS score was 2. DSA of the patient 3 demonstrated occipital sinusional area DAVF treated with surgical excision. More than one year after surgery, the patient was conscious with mRS score of 5.Conclusions:DAVF-induced bithalamic lesions is a rare disorder in which clinical presentations are not specific.When cranial CT or MRI demonstrating bithalamic lesions, MRA or CTA showing venous or venous sinus closely related with arteries or presenting with disturbance of consciousness or cognitive decline, DAVF should be considered. DSA is the gold standard for diagnosis of DAVF. Endovascular embolization and surgical excision are the main treatments of DAVF.