m^(6)A mRNA modification potentiates Th17 functions to inflame autoimmunity

N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.

Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development?

The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019(COVID-19) due to SARSCoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARSCoV-2 infection is a critical determinant for patients’ outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China

Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.

Photosensitizer conjugate-functionalized poly(hexamethylene guanidine) for potentiated broad-spectrum bacterial inhibition and enhanced biocompatibility

Pathogen infection is the main cause of human morbidity and death.Traditional antibiotics usually sterilize bacteria in chemical ways,which tends to develop serious antibiotic resistance.Cationic polymers exhibit good bacterial inhibition with less resistance,but often face severe cytotoxicity toward normal cells.The optimization of polymeric antimicrobials for enhanced bactericidal capacity and improved biocompatibility is quite meaningful.In addition,photodynamic therapy(PDT) is a therapeutic modality with less susceptibility to develop resistance.Herein,a typical commercial polymeric antimicrobial,polyhexamethylene guanidine(PHMG) was selected for current proof-of-concept optimization due to its excellent bactericidal capacity but moderate biocompatibility.Eosin-Y(EoS)was copolymerized to afford EoS-labeled polymer conjugates,poly(2-(dimethylamino) ethyl methacrylate-co-eosin),P(DMAEMA-co-EoS),which was conjugated with PHMG to afford a novel polymeric antimicrobial,P(DMAEMA-co-EoS)-b-PHMG-b-P(DMAEMA-co-EoS),noted as PEoS-PHMG.It could efficiently kill broad-spectrum bacteria by physical damage and photodynamic therapy.Compared with PHMG,the bacterial inhibition of PEoS-PHMG was potentiated after the functionalization.Furthermore,PEoS-PHMG exhibited low cytotoxicity and minimal hemolysis,which was demonstrated by cell viability assays toward LO2 cells and RAW 264.7 cells as well as hemolytic assays against red blood cells.These results confirmed that the resultant PEoS-PHMG could act as promising alternative antibacterial materials with excellent broad-spectrum bacterial inhibition and favorable biocompatibility.

High drug loading and pH-responsive nanomedicines driven by dynamic boronate covalent chemistry for potent cancer immunotherapy

Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NPBTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate-phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ-phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer-drug interaction for efficient drug delivery and controllable release.

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or polymersomes have been successfully developed,a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear.Herein,we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based(HPMPC)nanogel for tumor drug delivery.The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility,which leads to high and long-lasting accumulation in tumor tissue.Furthermore,HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment,which leads to the effective release of the loaded drug.Impressively,HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel,owing to the more complete drug release.Overall,the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects,which showed great potential as nanocarrier for advanced tumor drug delivery.

Heterologous mRNA vaccine booster increases neutralization of SARS-CoV-2 Omicron BA.2 variant

Dear Editor,Emerging epidemiology data indicate that the Omicron BA.2 sublineage is expected to become the dominant strain owing to its enhanced transmissibility.1 The BA.1 sublineage reduced the efficacy of neutralizing antibodies.2,3 The BA.2 sublineage may possess similar neutralizing antibody evasion.3 However,booster(3rd dose)vaccination strategies,or three exposures to the SARS-CoV2 spike protein through natural infection elicits strong neutralizing antibody responses.This raises the question of whether booster doses also elicit neutralizing antibody responses against BA.2.We present in this study the neutralization activity of serum from human recipients of homologous booster(three doses of CoronaVac inactivated vaccine)or heterologous booster(inactivated vaccine priming dose with BnT162b2 third dose)vaccine regimens against pseudovirus containing the Omicron BA.2 spike protein.We also evaluated the neutralizing activities of 6 monoclonal antibodies,and serum from monkeys vaccinated with a recombinant RBD protein vaccine.Finally,we also evaluated cell entry mediated by the Omicron BA.2 spike protein.