ABSTRACT
BACKGROUND: Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity. METHODS: The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo. RESULTS: MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently. CONCLUSION: The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.
Subject(s)
Antiviral Agents , Nanoparticle Drug Delivery System , Pneumonia/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cytomegalovirus , Cytomegalovirus Infections/drug therapy , Fatty Acids, Monounsaturated/chemistry , Foscarnet/pharmacology , Foscarnet/therapeutic use , Ganciclovir/pharmacology , Ganciclovir/therapeutic use , Humans , Inflammation/drug therapy , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Quaternary Ammonium Compounds/chemistry , Stem CellsSubject(s)
Adjuvants, Immunologic/chemistry , COVID-19/immunology , SARS-CoV-2/immunology , Viral Vaccines/immunology , COVID-19/genetics , COVID-19/prevention & control , COVID-19/virology , Cations/chemistry , Cations/immunology , Chitosan/chemistry , Chitosan/immunology , Drug Carriers/chemistry , Fatty Acids, Monounsaturated/chemistry , Fatty Acids, Monounsaturated/immunology , Humans , Polyethyleneimine/chemistry , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/immunology , Viral Vaccines/chemistryABSTRACT
Nanomedicine has demonstrated a substantial role in vaccine development against severe acute respiratory syndrome coronavirus (SARS-CoV-2 and COVID-19). Although nanomedicine-based vaccines have now been validated in millions of individuals worldwide in phase 4 and tracking of sex-disaggregated data on COVID-19 is ongoing, immune responses that underlie COVID-19 disease outcomes have not been clarified yet. A full understanding of sex-role effects on the response to nanomedicine products is essential to building an effective and unbiased response to the pandemic. Here, we exposed model lipid nanoparticles (LNPs) to whole blood of 18 healthy donors (10 females and 8 males) and used flow cytometry to measure cellular uptake by circulating leukocytes. Our results demonstrated significant differences in the uptake of LNP between male and female natural killer (NK) cells. The results of this proof-of-concept study show the importance of recipient sex as a critical factor which enables researchers to better consider sex in the development and administration of vaccines for safer and more-efficient sex-specific outcomes.
Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , SARS-CoV-2/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/chemistry , Drug Compounding/methods , Fatty Acids, Monounsaturated/chemistry , Female , Healthy Volunteers , Humans , Immunogenicity, Vaccine , Liposomes , Male , Pandemics/prevention & control , Quaternary Ammonium Compounds/chemistry , Sex Factors , Treatment OutcomeABSTRACT
Hybrid nanoparticles from lipidic and polymeric components were assembled to serve as vehicles for the transfection of messenger RNA (mRNA) using different portions of the cationic lipid DOTAP (1,2-Dioleoyl-3-trimethylammonium-propane) and the cationic biopolymer protamine as model systems. Two different sequential assembly approaches in comparison with a direct single-step protocol were applied, and molecular organization in correlation with biological activity of the resulting nanoparticle systems was investigated. Differences in the structure of the nanoparticles were revealed by thorough physicochemical characterization including small angle neutron scattering (SANS), small angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). All hybrid systems, combining lipid and polymer, displayed significantly increased transfection in comparison to lipid/mRNA and polymer/mRNA particles alone. For the hybrid nanoparticles, characteristic differences regarding the internal organization, release characteristics, and activity were determined depending on the assembly route. The systems with the highest transfection efficacy were characterized by a heterogenous internal organization, accompanied by facilitated release. Such a system could be best obtained by the single step protocol, starting with a lipid and polymer mixture for nanoparticle formation.