Robust induction of TRMs by combinatorial nanoshells confers cross-strain sterilizing immunity against lethal influenza viruses.

Antigen-specific lung-resident memory T cells (TRMs) constitute the first line of defense that mediates rapid protection against respiratory pathogens and inspires novel vaccine designs against infectious pandemic threats, yet effective means of inducing TRMs, particularly via non-viral vectors, remain challenging. Here, we demonstrate safe and potent induction of lung-resident TRMs using a biodegradable polymeric nanoshell that co-encapsulates antigenic peptides and TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) in a virus-mimicking structure. Through subcutaneous priming and intranasal boosting, the combinatorial nanoshell vaccine elicits prominent lung-resident CD4+ and CD8+ T cells that surprisingly show better durability than live viral infections. In particular, nanoshells containing CpG-ODN and a pair of conserved class I and II major histocompatibility complex-restricted influenza nucleoprotein-derived antigenic peptides are demonstrated to induce near-sterilizing immunity against lethal infections with influenza A viruses of different strains and subtypes in mice, resulting in rapid elimination of replicating viruses. We further examine the pulmonary transport dynamic and optimal composition of the nanoshell vaccine conducive for robust TRM induction as well as the benefit of subcutaneous priming on TRM replenishment. The study presents a practical vaccination strategy for inducing protective TRM-mediated immunity, offering a compelling platform and critical insights in the ongoing quest toward a broadly protective vaccine against universal influenza as well as other respiratory pathogens.

Nanotechnology advances in pathogen- and host-targeted antiviral delivery: multipronged therapeutic intervention for pandemic control.

The COVID-19 pandemic's high mortality rate and severe socioeconomic impact serve as a reminder of the urgent need for effective countermeasures against viral pandemic threats. In particular, effective antiviral therapeutics capable of stopping infections in its tracks is critical to reducing infection fatality rate and healthcare burden. With the field of drug delivery witnessing tremendous advancement in the last two decades owing to a panoply of nanotechnology advances, the present review summarizes and expounds on the research and development of therapeutic nanoformulations against various infectious viral pathogens, including HIV, influenza, and coronaviruses. Specifically, nanotechnology advances towards improving pathogen- and host-targeted antiviral drug delivery are reviewed, and the prospect of achieving effective viral eradication, broad-spectrum antiviral effect, and resisting viral mutations are discussed. As several COVID-19 antiviral clinical trials are met with lackluster treatment efficacy, nanocarrier strategies aimed at improving drug pharmacokinetics, biodistributions, and synergism are expected to not only contribute to the current disease treatment efforts but also expand the antiviral arsenal against other emerging viral diseases.

Nanomedicinal delivery of stimulator of interferon genes agonists: recent advances in virus vaccination.

The discovery of stimulator of interferon genes (STING) and their agonists as primary components that link antiviral innate and adaptive immunity has motivated growing research on STING agonist-mediated immunotherapy and vaccine development. To overcome the delivery challenge in shuttling highly polar STING agonists, typically in the form of cyclic dinucleotides, to target cells and to STING proteins in cellular cytosol, numerous nanoformulation strategies have been implemented for effective STING activation. While many STING-activating nanoparticles are developed to enhance anticancer immunotherapy, their adoption as vaccine adjuvant has vastly propelled antiviral vaccination efforts against challenging public health threats, including HIV, influenza and coronaviruses. In light of the COVID-19 pandemic that has thrusted vaccine development into the public spotlight, this review highlights advances in nanomedicinal STING agonist delivery with an emphasis on their applications in antiviral vaccination.

Neutralizing antibody response elicited by SARS-CoV-2 receptor-binding domain.

A safe and effective vaccine candidate is urgently needed for the ongoing COVID-19 pandemic, caused by SARS-CoV-2. Here we report that recombinant SARS-CoV-2 RBD protein immunization in mice is able to elicit a strong antibody response and potent neutralizing capability as measured using live or pseudotyped SARS-CoV-2 neutralization assays.