Improvement of B Cell Responses by an HIV-1 Amphiphilic Polymer Nanovaccine.

The human immunodeficiency virus (HIV) has infected over 84 million people since its discovery and is a huge threat to human health. While an HIV vaccine is urgently needed to curb this devastating pandemic, it has been notoriously difficult to develop, partly due to the extraordinary high level of genetic variation of HIV. We designed a new HIV-1 envelope glycoprotein nanoparticle (Env/NP) vaccine using amphiphilic polymers. The Env/NP vaccine induced more potent and broader neutralizing activities against multiple HIV-1 subtypes. Moreover, it elicits similar neutralizing antibody responses after the storage at -80 °C, 4 °C or room temperature post lyophilization. These results demonstrate that the new Env/NP vaccine not only improves the HIV vaccine immune responses but also is stable under different storage conditions. This new nanovaccine approach can readily apply to other protein-based vaccines.

Erratum: General method to stabilize mesophilic proteins in hyperthermal water.

[This corrects the article DOI: 10.1016/j.isci.2021.102503.].

Bioresponsive nanomedicines based on dynamic covalent bonds.

Trends in the development of modern medicine necessitate the efficient delivery of therapeutics to achieve the desired treatment outcomes through precise spatiotemporal accumulation of therapeutics at the disease site. Bioresponsive nanomedicine is a promising platform for this purpose. Dynamic covalent bonds (DCBs) have attracted much attention in studies of the fabrication of bioresponsive nanomedicines with an abundance of combinations of therapeutic modules and carrier function units. DCB-based nanomedicines could be designed to maintain biological friendly synthesis and site-specific release for optimal therapeutic effects, allowing the complex to retain an integrated structure before accumulating at the disease site, but disassembling into individual active components without compromising function in the targeted organs or tissues. In this review, we focus on responsive nanomedicines containing dynamic chemical bonds that can be cleaved by various specific stimuli, enabling achievement of targeted drug release for optimal therapy in various diseases.

General method to stabilize mesophilic proteins in hyperthermal water.

The stability of protein structures and biological functions at normal temperature is closely linked with the universal aqueous environment of organisms. Preserving bioactivities of proteins in hyperthermia water would expand their functional capabilities beyond those in native environments. However, only a limited number of proteins derived from hyperthermophiles are thermostable at elevated temperatures. Triggered by this, here we describe a general method to stabilize mesophilic proteins in hyperthermia water. The mesophilic proteins, protected by amphiphilic polymers with multiple binding sites, maintain their secondary and tertiary structures after incubation even in boiling water. This approach, outside the conventional environment for bioactivities of mesophilic proteins, provides a general strategy to dramatically increase the Tm (melting temperature) of mesophilic proteins without any changes to amino sequences of the native proteins. Current work offers a new insight with protein stability engineering for potential application, including vaccine storage and enzyme engineering.

Protein-drug conjugate programmed by pH-reversible linker for tumor hypoxia relief and enhanced cancer combination therapy.

Combining functional proteins with small molecular drugs into one entity may endow distinct synergistic advantages. However, on account of completely different physicochemical properties of such payloads, co-delivery through systemic administration for therapeutic purpose is challenging. Herein, we designed the protein-drug conjugate HSAP-DC-CAT (human serum albumin/Pt (IV)-dibenzocyclooctyne/chlorin e6-catalase) by modification of CAT and cisplatin pro-drug loaded HSA with pH-sensitive azide linker 3-(azidomethyl)-4-methyl-2,5-furandione (AzMMMan) followed by click chemistry assembly with DC. The dynamic covalent bonds between linker and proteins, on the one hand, can bridge proteins and small molecular drugs in the intermediate state for systemic delivery in the harsh in vivo environment; on the other hand, it can trigger traceless cleavage and release of drugs and proteins with full bioactivity in acidic microenvironment of tumor. The multifunctional HSAP-DC-CAT provides efficient cytosolic transduction in vitro, excellent blood half-lives after systemic administration, and significant antitumor outcome via integrated cisplatin-based chemotherapy and Ce6-based photodynamic therapy enhanced by catalase-induced manipulation of tumor hypoxia microenvironment. This study describes a universal formulation strategy for protein and small molecular drug by a bifunctional linker through amide reaction and click chemistry, with traceless in vivo release of therapeutic units.

Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response.

PURPOSE: Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain. METHODS: A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses. RESULTS: Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group. CONCLUSION: This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.

Cytotoxic seco-cytochalasins from an endophytic Aspergillus sp. harbored in Pinellia ternata tubers.

Six new seco-cytochalasins A-F (1-6), two new asperlactones G-H (7-8) along with three known cytochalasins (9-11) were isolated from the solid cultures of an endophytic fungus Aspergillus sp. Their structures were elucidated by comprehensive spectral analysis, and their absolute configurations were determined through Mo2(OCOCH3)4-induced electronic circular dichroism (ECD) spectra and Rh2(OCOCF3)4-induced ECD experiment. Compounds 5 and 6 were rare seco-cytochalasins possessing an α, ß-unsaturated furanone structure in their side-chains. These isolates exhibited cytotoxicity against human lung cancer A-549 cell line with IC50 values ranging from 7.8 to 70.2 µM. At the concentration of 16 µM, compound 4 also exerted a 3-fold enhancement of doxorubicin susceptibility on doxorubicin-resistant human breast cancer (MCF-7/DOX) cell line.