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Showing papers on "In vivo published in 2022"


Journal ArticleDOI
07 Jan 2022-Science
TL;DR: A therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs) was developed.
Abstract: Description Making CAR T cells in vivo Cardiac fibrosis is the stiffening and scarring of heart tissue and can be fatal. Rurik et al. designed an immunotherapy strategy to generate transient chimeric antigen receptor (CAR) T cells that can recognize the fibrotic cells in the heart (see the Perspective by Gao and Chen). By injecting CD5-targeted lipid nanoparticles containing the messenger RNA (mRNA) instructions needed to reprogram T lymphocytes, the researchers were able to generate therapeutic CAR T cells entirely inside the body. Analysis of a mouse model of heart disease revealed that the approach was successful in reducing fibrosis and restoring cardiac function. The ability to produce CAR T cells in vivo using modified mRNA may have a number of therapeutic applications. —PNK In vivo generation of CAR T cells by delivery of modified mRNA improves recovery in a mouse model of heart failure. Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.

274 citations


Journal ArticleDOI
01 Jan 2022-Cell
TL;DR: In this paper , the authors report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins.

161 citations


Journal ArticleDOI
TL;DR: Left-handed nanoparticles show substantially higher efficiency compared with their right-handed counterparts as adjuvants for vaccination against the H9N2 influenza virus, opening a path to the use of nanoscale chirality in immunology.

149 citations


Journal ArticleDOI
TL;DR: Cur loaded tetrahedral framework nucleic acids (Cur-TFNAs) were synthesized to deliver Cur and present better anti-inflammatory effect than free Cur both in vivo and in vitro experiments through the determination of inflammation-related cytokines expression.

116 citations


Journal ArticleDOI
Yunfeng Lin1
TL;DR: In this paper , a tetrahedral framework nucleic acids (Cur-TFNAs) were synthesized to deliver Cur. Compared with free Cur, Cur-TFNs exhibit better anti-inflammatory effect than free Cur both in vivo and in vitro experiments through the determination of inflammation-related cytokines expression.

99 citations


Journal ArticleDOI
TL;DR: It is concluded that the four-nucleotide deletion is the pathological cause of NOA in patient P8944, and the inactivation of MSH5 causes defects in germ cell development in the mouse model.

93 citations


Journal ArticleDOI
TL;DR: In this paper , the authors report on the protection of two monoclonal antibody therapies (S309 and AZD7442) against SARS-CoV-2 Omicron lineage strains (BA.1, BA.2, and BA.1.1).
Abstract: Abstract Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2) in prophylactic and therapeutic settings. Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human FcγR transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.

85 citations


Journal ArticleDOI
TL;DR: The T‐probe system efficiently and accurately images tumor‐related biomarkers in vitro and in vivo, thereby demonstrating great potential for clinical diagnosis and therapeutic applications.
Abstract: Rapid and efficient tools for early cancer detection have diagnostic and therapeutic value. Given that the DNA hairpin‐based hybridization chain reaction (HCR) is effective in detecting various biological targets, a tetrahedral framework DNA‐enhanced (TDN‐enhanced) HCR detection system (T‐probe system) is introduced for cancer‐related targets and its versatility is demonstrated by detecting intracellular target miRNA 21 and cellular membrane target nucleolin. Benefiting from the spatial confinement of the TDN, the T‐probe system demonstrates a high detection rate. It increases the reaction efficiency of nude hairpins in vitro while accurately and rapidly recognizing both membrane and intracellular cancer‐related targets in living cells. Furthermore, it exhibits superior fluorescence in vivo within 15 s of peripheral‐tumor injection and 10 min of tail‐vein injection. The T‐probe system efficiently and accurately images tumor‐related biomarkers in vitro and in vivo, thereby demonstrating great potential for clinical diagnosis and therapeutic applications.

75 citations


Journal ArticleDOI
TL;DR: In this article , a hybrid membranes-coated hollow copper sulfide nanoparticles (D-CuS@NR NPs) were fabricated for osteoarthritis (OA) treatment, which achieved the synergistic treatment of mild heating, prolonged circulation, and targeted delivery in this system.
Abstract: Osteoarthritis (OA), as a chronic degenerative joint disorder, has seriously affected the life quality of patients. Despite lots of drug treatment strategies that have been studied, the therapeutic effect is still unsatisfactory due to the lack of prolonged circulation life and targeted delivery ability. Recently, functional cell membranes modified nanoparticles have been explored to achieve high-efficiency drug delivery. Herein, neutrophil-erythrocyte hybrid membranes-coated dexamethasone sodium phosphate (Dexp)-loaded hollow copper sulfide nanoparticles (D-CuS@NR NPs) were fabricated for OA treatment. Generally, we achieved the synergistic treatment of mild-heating, prolonged circulation, and targeted delivery in this system. In particular, this biomimetic nanoparticle showed significant cytocompatibility and anti-inflammatory ability in vitro due to cell membrane coating and photothermal responsive drug release under NIR irradiation. Importantly, in vivo explorations revealed that D-CuS@NR NPs combined with photothermal treatment obtained an excellent therapy effect for preventing the OA process. Hence, this novel hybrid membranes-coated CuS NPs showed significant therapeutic efficacy by local warming and targeted drug delivery , which might become a promising drug delivery vehicle for improving the therapeutic effect of OA. • This nanoparticle possesses lots of advantages, including long circulation effect, excellent target ability, and well photothermal conversion efficiency. • Combined with NIR treatment, this drug loaded nanoparticle gained outstanding anti-inflammatory effect and ability to protect articular cartilage in vivo . • This drug loaded nanoparticle provides a promising platform for inflammation related diseases.

71 citations


Journal ArticleDOI
28 Jun 2022-Cell
TL;DR: In this article , the authors compared the benefits and drawbacks of different delivery modalities and highlighted opportunities for future improvements, since no single delivery modality is likely to be appropriate for every possible application.

66 citations


Journal ArticleDOI
Andrew E. Aplin1
TL;DR: SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence, displays high potency with balanced activation of all three target receptors as discussed by the authors .

Journal ArticleDOI
TL;DR: The success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene, is demonstrated and establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
Abstract: Significance The current application of messenger RNA (mRNA)-based technology has largely been confined to liver diseases because of the lack of a specific and efficient extrahepatic in vivo systemic mRNA delivery system. Here, we have developed a library of N-series lipid nanoparticles (LNPs) that could specifically regulate the protein composition of protein corona on the surface of LNPs, which allows specific delivery of mRNA to the lung. We further demonstrated that our lung-targeting LNP could effectively deliver mouse tuberous sclerosis complex 2 (Tsc2) mRNA into TSC2-null cells and restore its function, resulting in enhanced control of tumor burden in a preclinical model of lymphangioleiomyomatosis, a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography–mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.

Journal ArticleDOI
TL;DR: Itaconate and 4-octyl itaconate (OI) were shown to suppress the inflammatory response in pro-inflammatory "M1" macrophages and inhibit metabolic remodeling as mentioned in this paper .

Journal ArticleDOI
TL;DR: In this paper , a two-dimensional (2D) Pd-based nanozyme conjugated with a glucose oxidase (GOx) was used to induce the PA signal variation of endogenous molecules.
Abstract: Non-invasive visualization of dynamic molecular events in real-time via molecular imaging may enable the monitoring of cascade catalytic reactions in living systems, however effective imaging modalities and a robust catalytic reaction system are lacking. Here we utilize three-dimensional (3D) multispectral photoacoustic (PA) molecular imaging to monitor in vivo cascade catalytic therapy based on a dual enzyme-driven cyclic reaction platform. The system consists of a two-dimensional (2D) Pd-based nanozyme conjugated with glucose oxidase (GOx). The combination of nanozyme and GOx can induce the PA signal variation of endogenous molecules. Combined with the PA response of the nanozyme, we can simultaneously map the 3D PA signals of dynamic endogenous and exogenous molecules associated with the catalytic process, thus providing a real-time non-invasive visualization. We can also treat tumors under the navigation of the PA imaging. Therefore, our study demonstrates the imaging-guided potential of 3D multispectral PA imaging in feedback-looped cascade catalytic therapy.

Journal ArticleDOI
TL;DR: In this paper , a new multifunctional platform with the core-shell structure 5-ALA@UiO-66-NH-FAM@CP1 (ALA = 5aminolevulinic acid, CP1 = zirconium-pemetrexed (Zr-MTA)) has been performed.

Journal ArticleDOI
TL;DR: Wang et al. as mentioned in this paper found that METTL14 was downregulated in GC tissue samples, and its low expression acted as a prognostic factor of poor survival in patients with GC.
Abstract: N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression.The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses.We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC.Our findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

Journal ArticleDOI
TL;DR: A review of metal-based cancer drug candidates can be found in this paper , where the benefits and drawbacks regarding the activity and toxicity of the metalbased cancer drugs candidates are discussed.

Journal ArticleDOI
TL;DR: A review of metal-based cancer drug candidates can be found in this paper, where the benefits and drawbacks regarding the activity and toxicity of the metalbased cancer drugs candidates are discussed.

Journal ArticleDOI
TL;DR: The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.

Journal ArticleDOI
TL;DR: Ru1085 as mentioned in this paper is a metal-based metallacycle with an excitation at 808 nm and emission over 1000 nm, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity.
Abstract: Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications.

Journal ArticleDOI
TL;DR: The introduced in vivo printing strategy for wound healing applications is translational and convenient to use in any place, such as an operating room, and does not require expensive bioprinters or imaging modalities.

Journal ArticleDOI
TL;DR: Wang et al. as mentioned in this paper found that METTL14 was downregulated in GC tissue samples, and its low expression acted as a prognostic factor of poor survival in patients with GC.
Abstract: N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression.The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses.We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC.Our findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

Journal ArticleDOI
TL;DR: In this paper , the authors investigated the role of copper in radiotherapy and revealed new targets and treatment strategies for overcoming radioresistance in hepatocellular carcinoma (HCC) patients.

Journal ArticleDOI
TL;DR: In this article , a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides was developed to enhance systemic delivery of living bacteria therapies for treating a broad array of cancers.
Abstract: Living bacteria therapies have been proposed as an alternative approach to treating a broad array of cancers. In this study, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides that enhances systemic delivery. Based on a small RNA screen of capsular biosynthesis pathways, we constructed inducible synthetic gene circuits that regulate bacterial encapsulation in Escherichia coli Nissle 1917. These bacteria are capable of temporarily evading immune attack, whereas subsequent loss of encapsulation results in effective clearance in vivo. This dynamic delivery strategy enabled a ten-fold increase in maximum tolerated dose of bacteria and improved anti-tumor efficacy in murine models of cancer. Furthermore, in situ encapsulation increased the fraction of microbial translocation among mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system promises to enhance the therapeutic utility of living engineered bacteria for cancer.

Journal ArticleDOI
Zhengwei Mao1
TL;DR: In this article , a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE)-Pt) as building blocks.
Abstract: To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.

Journal ArticleDOI
TL;DR: In this paper , the compatibility of EAB sensors with standard sterilization and high-level disinfection techniques was investigated in the context of biomedical research and diagnosis, treatment, and monitoring of disease.
Abstract: Electrochemical aptamer-based (EAB) sensors encompass the only biosensor approach yet reported that is simultaneously: (1) independent of the chemical or enzymatic reactivity of its target, rendering it general; (2) continuous and real-time; and (3) selective enough to deploy in situ in the living body. Consistent with this, in vivo EAB sensors supporting the seconds-resolved, real-time measurement of multiple drugs and metabolites have been reported, suggesting the approach may prove of value in biomedical research and the diagnosis, treatment, and monitoring of disease. However, to apply these devices in long-duration animal models, much less in human patients, requires that they be free of any significant pathogen load. Thus motivated, here we have characterized the compatibility of EAB sensors with standard sterilization and high-level disinfection techniques. Doing so, we find that, while many lead to significant sensor degradation, treatment with CIDEX OPA (0.55% ortho-phthalaldehyde) leads to effective disinfection without causing any detectable loss in sensor performance.

Journal ArticleDOI
TL;DR: In this paper, a pH/reactive oxygen species (ROS) dual responsive injectable glycopeptide hydrogel based on phenylboronic acid-grafted oxidized dextran and caffeic acidgrafted e-polylysine was constructed, which exhibited inherent antibacterial and antioxidant capacities.

Journal ArticleDOI
TL;DR: In this paper , a pH/reactive oxygen species (ROS) dual responsive injectable glycopeptide hydrogel based on phenylboronic acid-grafted oxidized dextran and caffeic acidgrafted ε-polylysine was constructed, which exhibited inherent antibacterial and antioxidant capacities.

Journal ArticleDOI
TL;DR: In this paper , a new method to deliver PE to adult tissue, paving the way for in vivo gene-editing therapy using PE, was proposed, where split-PE was used to correct the majority of known human genetic disease-related mutations.

Journal ArticleDOI
TL;DR: In this article , a series of potent α-ketoamide-containing Mpro inhibitors were obtained using the Ugi four-component reaction and the prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively.
Abstract: Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2. An inhibitor of the SARS-CoV-2 main protease (Mpro), Y180, showed therapeutic efficacy against wild-type SARS-CoV-2 and its variants including Omicron after oral administration and improved survival in a humanized mouse model.