STING and TLR9 agonists synergistically enhance the immunogenicity of SARS-CoV-2 subunit vaccine

Vaccines that are reliable and efficacious are essential in the fight against the COVID-19 pandemic.In this study,we designed a dual-adjuvant system with two pathogen-associated molecular patterns(PAMPs),MnOx and CpG.This system can improve the retention of antigens at the injection site,facilitate pro-inflammatory cytokines secretion,further recruit and activate dendritic cells(DCs).As a result,antigens can be delivered to lymph nodes specifically,and adaptive immunity was strengthened.The immunized group showed an enhanced and broadened humoral and cellular immune response in systemic immunity and lung protection when combined with a tandem repeat-linked dimeric antigen version of the SARS-CoV-2 receptor binding domain(RBDdimer).Remarkably,even with a significant reduction in antigen dosage(three times lower)and a decrease in injection frequencies,our nanovaccine was able to produce the highest neutralizing antibody titers against various mutants.These titers were four-fold higher for the wild-type strain and two-fold higher for both the Beta and Omicron variants in comparison with those elicited by the Alum adjuvant group.In conclusion,our dual-adjuvant formulation presents a promising protein subunit-based candidate vaccine against SARS-CoV-2.

Engineering nanomedicines for immunogenic eradication of cancer cells:Recent trends and synergistic approaches

Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies including chemotherapy,radiotherapy,photodynamic,photothermal,magnetic,chemodynamic,sonodynamic and oncolytic therapy,have been developed to induce immunogenic cell death(ICD)of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response.However,many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response.Here,we outline the current state of using nanomedicines for boosting ICD of cancer cells.Moreover,synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints,phagocytosis,macrophage polarization,tumor hypoxia,autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed.We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses.Endoplasmic reticulum localized ICD,focused ultrasound hyperthermia,cell membrane camouflaged nanomedicines,amplified reactive oxygen species(ROS)generation,metallo-immunotherapy,ion modulators and engineered bacteria are among the most innovative approaches.Various challenges,merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment.The agonist cyclic dinucleotides(CDNs)of the stimulator of interferon gene(STING)are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity.However,the tumor immune efficacy of CDNs is limited by several factors,including relatively narrow cytokine production,inefficient delivery to STING,and rapid clearance.In addition,a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect.To address this problem,two or more agonist molecules are often used together to synergistically enhance immune efficacy.In this work,we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8(TLR7/8)agonist 522 produced a broader cytokine response.Subsequently,we developed multicomponent nanovaccines(MCNVs)consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules.These MCNVs activate bone marrow-derived dendritic cells(BMDCs)to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor Tcell responses.In in vivo experiments,we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes,resulting in significant tumor regression and,notably,a 100%survival rate in mice through 25 days without other partnering therapies.These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.