Ionizable drug delivery systems for efficient and selective gene therapy.

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function. However, a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells. To be excited, the development of ionizable drug delivery systems (IDDSs) has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019 (COVID-19) in 2021. Compared with conventional cationic gene vectors, IDDSs can decrease the toxicity of carriers to cell membranes, and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures. Despite the progress, there remain necessary requirements for designing more efficient IDDSs for precise gene therapy. Herein, we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms. The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of pDNA and four kinds of RNA. In particular, organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity. We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future, and indicate ideas for developing next generation gene vectors.

Lyophilized mRNA-lipid nanoparticles vaccine with long-term stability and high antigenicity against SARS-CoV-2 (preprint)

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, due to the poor stability, most current mRNA delivery platforms need to be stored at -20 {degrees}C or -70 {degrees}C. Here we present lyophilized thermostable mRNA loaded lipid nanoparticles, which could be stored at room temperature with long-term stability. We demonstrate the applicability of lyophilization techniques to different mRNA sequences and lipid components. Three lyophilized vaccines targeting wild-type, Delta and Omicron SARS-CoV-2 variant were prepared and demonstrated to be able induce high-level of IgG titer and neutralization response. In the Delta challenge in vivo experiment, the lyophilized mRNA vaccine successfully protected the mice from infection and clear the virus. This lyophilization platform could significantly improve the accessibility of mRNA vaccine or therapeutics, particularly in remote regions.

Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan (preprint)

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conducted a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and tested specific antibody response. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. RBD-IgG kinetics displayed a gradually downward trend, the titer started to stabilize after 9 months and decreased by 68.1% compared with the 1st month. Moreover, male plasma donors produced more RBD-IgG than female plasma donors and patient age positively correlated with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers was also identified. This study is essential for understanding SARS-CoV-2-induced immune memory to develop vaccine and therapeutics.

Weibo-COV: A Large-Scale COVID-19 Social Media Dataset from Weibo (preprint)

With the rapid development of COVID-19 around the world, people are requested to maintain "social distance" and "stay at home". In this scenario, extensive social interactions transfer to cyberspace, especially on social media platforms like Twitter and Sina Weibo. People generate posts to share information, express opinions and seek help during the pandemic outbreak, and these kinds of data on social media are valuable for studies to prevent COVID-19 transmissions, such as early warning and outbreaks detection. Therefore, in this paper, we release a novel and fine-grained large-scale COVID-19 social media dataset collected from Sina Weibo, named Weibo-COV, contains more than 40 million posts ranging from December 1, 2019 to April 30, 2020. Moreover, this dataset includes comprehensive information nuggets like post-level information, interactive information, location information, and repost network. We hope this dataset can promote studies of COVID-19 from multiple perspectives and enable better and rapid researches to suppress the spread of this pandemic.

Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment (preprint)

Background Coronavirus infectious disease 2019 (COVID-19) has developed into a global pandemic. It is essential to investigate the clinical characteristics of COVID-19 and uncover potential risk factors for severe disease to reduce the overall mortality rate of COVID-19. Methods Sixty-one critical COVID-19 patients admitted to the intensive care unit (ICU) and 93 severe non-ICU patients at Huoshenshan Hospital (Wuhan, China) were included in this study. Medical records, including demographic, platelet counts, heparin-involved treatments, heparin-induced thrombocytopenia-(HIT) related laboratory tests, and fatal outcomes of COVID-19 patients were analyzed and compared between survivors and nonsurvivors. Findings Sixty-one critical COVID-19 patients treated in ICU included 15 survivors and 46 nonsurvivors. Forty-one percent of them (25/61) had severe thrombocytopenia, with a platelet count (PLT) less than 50x109/L, of whom 76% (19/25) had a platelet decrease of >50% compared to baseline; 96% of these patients (24/25) had a fatal outcome. Among the 46 nonsurvivors, 52.2% (24/46) had severe thrombocytopenia, compared to 6.7% (1/15) among survivors. Moreover, continuous renal replacement therapy (CRRT) could induce a significant decrease in PLT in 81.3% of critical CRRT patients (13/16), resulting in a fatal outcome. In addition, a high level of anti-heparin-PF4 antibodies, a marker of HIT, was observed in most ICU patients. Surprisingly, HIT occurred not only in patients with heparin exposure, such as CRRT, but also in heparin-naive patients, suggesting that spontaneous HIT may occur in COVID-19. Interpretation Anti-heparin-PF4 antibodies are induced in critical COVID-19 patients, resulting in a progressive platelet decrease. Exposure to a high dose of heparin may trigger further severe thrombocytopenia with a fatal outcome. An alternative anticoagulant other than heparin should be used to treat COVID-19 patients in critical condition.

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation (preprint)

An excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo. Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study (preprint)

Currently, there are no approved specific antiviral agents for 2019 novel coronavirus disease (COVID-19). In this study, ten severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 days after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 days. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 days. Several parameters tended to improve as compared to pre-transfusion, including increased lymphocyte counts (0.65*109/L vs. 0.76*109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesionswithin 7 days. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was welltolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.