Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform.

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

Stay-at-home and face mask policy intentions inconsistent with incidence and fatality during the US COVID-19 pandemic.

During the COVID-19 pandemic, many states imposed stay-at-home (SAH) and mandatory face mask (MFM) orders to supplement the United States CDC recommendations. The purpose of this study was to characterize the relationship between SAH and MFM approaches with the incidence and fatality of COVID-19 during the pandemic period until 23 August 2020 (about 171 days), the period with no vaccines or specific drugs that had passed the phase III clinical trials yet. States with SAH orders showed a potential 50-60% decrease in infection and fatality during the SAH period (about 45 days). After normalization to population density, there was a 44% significant increase in the fatality rate in no-SAH + no-MFM states when compared to SAH + MFM. However, many results in this study were inconsistent with the intent of public health strategies of SAH and MFM. There were similar incidence rates (1.41, 1.81, and 1.36%) and significant differences in fatality rates (3.40, 2.12, and 1.25%; p < 0.05) and mortality rates (51.43, 34.50, and 17.42 per 100,000 residents; p < 0.05) among SAH + MFM, SAH + no-MFM, and no-SAH + no-MFM states, respectively. There were no significant differences in total positive cases, average daily new cases, and average daily fatality when normalized with population density among the three groups. This study suggested potential decreases in infection and fatality with short-term SAH order. However, SAH and MFM orders from some states' policies probably had limited effects in lowering transmission and fatality among the general population. At the policy-making level, if contagious patients would not likely be placed in strict isolation and massive contact tracing would not be effective to implement, we presume that following the CDC's recommendations with close monitoring of healthcare capacity could be appropriate in helping mitigate the COVID-19 disaster while limiting collateral socioeconomic damages.

Multidomain peptide hydrogel adjuvants elicit strong bias towards humoral immunity.

Adjuvants play a critical role in enhancing vaccine efficacy; however, there is a need to develop new immunomodulatory compounds to address emerging pathogens and to expand the use of immunotherapies. Multidomain peptides (MDPs) are materials composed of canonical amino acids that form injectable supramolecular hydrogels under physiological salt and pH conditions. MDP hydrogels are rapidly infiltrated by immune cells in vivo and have previously been shown to influence cytokine production. Therefore, we hypothesized that these immunostimulatory characteristics would allow MDPs to function as vaccine adjuvants. Herein, we demonstrate that loading antigen into MDP hydrogels does not interfere with their rheological properties and that positively charged MDPs can act as antigen depots, as demonstrated by their ability to release ovalbumin (OVA) over a period of 7-9 days in vivo. Mice vaccinated with MDP-adjuvanted antigen generated significantly higher IgG titers than mice treated with the unadjuvanted control, suggesting that these hydrogels potentiate humoral immunity. Interestingly, MDP hydrogels did not elicit a robust cellular immune response, as indicated by the lower production of IgG2c and smaller populations of tetramer-positive CD8+ T splenocytes compared to mice vaccinated alum-adjuvanted OVA. Together, the data suggest that MDP hydrogel adjuvants strongly bias the immune response towards humoral immunity while evoking a very limited cellular immune response. As a result, MDPs may have the potential to serve as adjuvants for applications that benefit exclusively from humoral immunity.