The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

As the world braces to enter its fourth year of the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to the treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using three separate administration methods, namely, intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound K D of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.

Drug-resistant bacterial infections are a growing cause of illness and death globally. Current methods of treatment are not only proving less effective but also perpetuate evolution of new resistance. Here we propose, through an in vivo model, a new treatment for drug-resistant bacterial infection that uses semiconductor nanoparticles, called quantum dots (QDs), that can be activated by light to produce superoxide to specifically and effectively kill drug-resistant bacteria. We adapt this technology for in vivo assessment of toxicity and treatment of a subcutaneous infection in mice. As our cadmium telluride QDs with 2.4 eV band gap (CdTe-2.4 QDs) are activated by blue light, we engineered LED patches to adhere to the infection site on mice, thus providing the light necessary for the activity of injected QDs and treatment of the infection. We show, through assessment of body weight, histology, and inflammation and oxidative stress markers in serum, that the CdTe-2.4 QDs are nontoxic at concentrations that reduce drug-resistant bacterial viability in subcutaneous abscesses. Further, CdTe-2.4 QDs did not accumulate in the body and were safely excreted in urine via renal clearance. CdTe-2.4 QD treatment decreased abscess viability by as much as 7 orders of magnitude. We thus propose an alternative treatment approach for drug-resistant topical infections: the injection of a low concentration of QDs and the application of an adhesive patch comprising only an LED and a battery. This treatment could revolutionize last-resort treatments of burn wounds, cellulitis, and other skin infections.

The increasing prevalence of drug-resistant bacterial strains is causing illness and death in an unprecedented number of people around the globe. Currently implemented small-molecule antibiotics are both increasingly less efficacious and perpetuating the evolution of resistance. Here, we propose a new treatment for drug-resistant bacterial infection in the form of indium phosphide quantum dots (InP QDs), semiconductor nanoparticles that are activated by light to produce superoxide. We show that the superoxide generated by InP QDs is able to effectively kill drug-resistant bacteria in vivo to reduce subcutaneous abscess infection in mice without being toxic to the animal. Our InP QDs are activated by near-infrared wavelengths with high transmission through skin and tissues and are composed of biocompatible materials. Body weight and organ tissue histology show that the QDs are nontoxic at a macroscale. Inflammation and oxidative stress markers in serum demonstrate that the InP QD treatment did not result in measurable effects on mouse health at concentrations that reduce drug-resistant bacterial viability in subcutaneous abscesses. The InP QD treatment decreased bacterial viability by over 3 orders of magnitude in subcutaneous abscesses formed in mice. These InP QDs thus provide a promising alternative to traditional small-molecule antibiotics, with the potential to be applied to a wide variety of infection types, including wound, respiratory, and urinary tract infections.

As the world braces to enter its third year in the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer,™ a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed after three separate administration methods, namely intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound KD of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.

Multidrug‐resistant (MDR) bacterial infections remain a major threat to public health, despite strides made in antibiotic development in the past century. The rise of MDR infections has demonstrated the dire need for new treatment strategies against infectious disease. MDR bacteria are predicted to cause ten million deaths annually worldwide by 2050, more than all cancers combined, unless significant strides are made in treatment options. While pharmaceutical companies devote years to develop a single drug for a single ailment, bacteria are quick to adapt, and MDR bacterial strains appear within only a couple years of the release of a new antibiotic. Our antibiotic discovery pipelines must accommodate the necessary shift away from traditional small molecule therapies toward more adaptive drugs. Here, we investigate new ways of combating MDR bacteria and apply those methods in vivo to optimize them for clinical use. We present a novel method for the treatment of infections caused by MDR bacteria: antibiotic photoactivated semiconductor nanoparticles called quantum dots (QDs). Photoactivated QDs kill bacteria by producing superoxide, which targets iron clusters in bacterial cells, and additionally have been shown to potentiate the activity of antibiotics against resistant bacteria. We have previously shown that this specific generation of superoxide allows for killing of bacterial cells without causing toxicity to surrounding mammalian cells in vitro. Indium phosphide (InP) QDs injected subcutaneously into mice caused no measured toxicity, measured through body weight, organ histology, and inflammation and oxidative stress markers in serum, to the host animal after six consecutive days of treatment. InP QDs are activated by near‐infrared (NIR) light, which was provided to the injection site using high‐intensity LEDs. We then used InP QDs to treat subcutaneous abscesses of MDR clinical isolate Escherichia coli in mice. As NIR light has high transmittance through skin and tissue, QDs injected under the skin were sufficiently activated for bacterial killing. We observed decreased bacterial count by QD dosages of 2 and 4 μM compared to PBS treatment. A 6000‐fold drop in abscess bacterial viability was observed in mice treated with 4 μM QDs compared to PBS control. This novel approach to treatment of infectious disease could provide necessary alternatives to small‐molecule drugs. The QDs offer a new method of using superoxide to kill bacteria, including bacteria that have developed resistance to small‐molecule drugs. Our QDs could revolutionize last‐resort treatments of burn and wound infections, with the potential to be expanded to other infection types.

Superoxide-producing CdTe-2.4 eV nanoparticles treat an intracellular infection of Salmonella in a 2D preosteoblast bone infection model.

The COVID‐19 pandemic has demonstrated the dire need for new treatment strategies against infectious disease. COVID‐19 has caused over 766,000 deaths in the United States. While multiple vaccines have been developed, the occurrence of new variant strains and the low rates of vaccination in some regions threaten the efficacy of these vaccines in keeping the global population safe. Current treatments for patients with severe COVID‐19 mainly focus on controlling the immune response or providing organ support, but while most patients recover from the disease, lasting effects may continue to disrupt patient lives and global fatalities remain high. Here, we investigate the feasibility of using a novel antisense molecule as an antiviral against SARS‐CoV‐2. The antisense antiviral, called a nanoligomer, has been developed from Sachi Bioworks’ proprietary synthetic nucleic acid‐based drug discovery platform. The nanoligomers bind to specific DNA or mRNA sequences and offer high specificity and superior transport into cells. These molecules target the SARS‐CoV‐2 genome to prevent translation of the RNA‐dependent RNA polymerase ubiquitous in all RNA viruses, thus preventing viral replication. These antivirals were assessed for toxicity in mice using intranasal, intraperitoneal, and intravenous administration. Intranasal drug administration maximizes treatment concentration at the respiratory infection site, while intraperitoneal and intravenous administration gives further insight on biodistribution of the compound and responses in other organs. Data shows a favorable safety profile in our murine model. Body weight of mice was unaffected by administration of nanoligomers. Serum parameters and organ histology indicated no changes compared to control mice. Cytokine levels remained largely below the level of detection, suggesting that the nanoligomers did not cause any inflammation or immune response in the mice. Further, biodistribution studies showed high initial bioavailability to the lungs, followed by rapid renal clearance and urinary excretion. The nanoligomers therefore show traits of being a safe therapeutic with favorable bioavailability and desirable clearance post‐treatment. The antiviral presented is highly adaptable and the sequence may be adjusted to target new variants of respiratory viruses. The antisense sequence can additionally be designed to target a wide variety of DNA, mRNA, or miRNA, including host sequences linked to severe inflammatory responses to COVID‐19. A second nanoligomer we have designed and tested targets a human miRNA that has been shown to be upregulated in patients with severe symptoms in response to a SARS‐CoV‐2 infection. Binding this miRNA and preventing its action within the host may prevent damage to the host body caused by the immune response. The ability of these molecules to target either the virus itself or alleviate harmful host responses to infection makes nanoligomers a highly versatile treatment option for COVID‐19.