Aptamer-Assisted Blockade of the Immune Suppressor Sialic Acid-Binding Immunoglobulin-Like Lectin-15 for Cancer Immunotherapy.

The percentage of low response and adaptive resistance to current antibody-based immune checkpoint blockade (ICB) therapy requires the development of novel immunotherapy strategies. Here, we developed an aptamer-assisted immune checkpoint blockade (Ap-ICB) against sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15), a novel immune suppressor broadly upregulated on cancer cells and tumor infiltrating myeloid cells, which is mutually exclusive of programmed cell death ligand 1 (PD-L1). Using protein aptamer selection, we identified WXY3 aptamer with high affinity against Siglec-15 protein/Siglec-15 positive cells. We demonstrated that WXY3 aptamer rescued antigen-specific T cell responses in vitro and in vivo. Importantly, the WXY3 Ap-ICB against Siglec-15 amplified anti-tumor immunity in the tumor microenvironment and inhibited tumor growth/metastasis in syngeneic mouse model, which may result from enhanced macrophage and T cell functionality. In addition, by using aptamer-based spherical nucleic acids, we developed a synergetic ICB strategy of multivalent binding and steric hindrance, which further improves the in vivo anti-tumor effect. Taken together, our results support Ap-ICB targeted Siglec-15 as a potential strategy for normalization cancer immunotherapy.

Spherical Neutralizing Aptamer Inhibits SARS-CoV-2 Infection and Suppresses Mutational Escape.

New neutralizing agents against SARS-CoV-2 and associated mutant strains are urgently needed for the treatment and prophylaxis of COVID-19. Herein, we develop a spherical cocktail neutralizing aptamer-gold nanoparticle (SNAP) to block the interaction between the receptor-binding domain (RBD) of SARS-CoV-2 and host ACE2. With the multivalent aptamer assembly as well as the steric hindrance effect of the gold scaffold, SNAP exhibits exceptional binding affinity against the RBD with a dissociation constant of 3.90 pM and potent neutralization against authentic SARS-CoV-2 with a half-maximal inhibitory concentration of 142.80 fM, about 2 or 3 orders of magnitude lower than that of the reported neutralizing aptamers and antibodies. More importantly, the synergetic blocking strategy of multivalent multisite binding and steric hindrance ensures broad neutralizing activity of SNAP, almost completely blocking the infection of three mutant pseudoviruses. Overall, the SNAP strategy provides a new direction for the development of antivirus agents against SARS-CoV-2 and other emerging coronaviruses.

In Situ Visualization of PD-L1-Specific Glycosylation on Tissue Sections.

Immune checkpoint therapy has provided a weapon against cancer, but its response rate has been extremely low due to the lack of effective predictors. Herein, we developed a FRET strategy based on lectin for glycan labeling and an aptamer for PD-L1 antigen recognition for visualization of PD-L1-specific glycosylation (FLAG). The FLAG strategy combines the PD-L1 aptamer, which efficiently labels the PD-L1 polyantigen with smaller steric hindrance than the PD-L1 antibody, and metabolism-free lectin labeling for glycosylation. As a result, the FLAG strategy enables in situ visualization of PD-L1-specific glycosylation on the tissue section while maintaining the spatial context and tissue architecture. Due to nonmetabolic labeling, the FLAG strategy revealed that the tissue level of PD-L1-specific glycosylation is correlated with the efficacy of PD-1/PD-L1 therapy. Overall, the FLAG strategy provides a powerful tool for revealing the significance of PD-L1 glycosylation, offering the unprecedented potential for immunophenotypic differential analysis to predict the immunotherapy response.