Mesoporous Silica Nanoparticles with Extra-Large Pores for Boosting Antigen Presentation and PD-L1 Immune Checkpoint...

Dendritic cell (DC)-based cancer immunotherapies have gained considerable attention over recent decades, owing to their potent antigen-presentation capacity. To elicit antigen-specific adaptive immune responses, it is essential to employ an efficient antigen delivery system that can preferentially accumulate at the tumor microenvironment (TME), enhance antigen presentation by DCs, and promote strong activation of naive T cells. However, inefficient delivery of tumor-specific antigens hinders the antitumor response. In addition, the immunosuppressive TME upregulates PD-L1 expression in cancer and intratumoral DCs, facilitating immune evasion by cancer cells. The PD-L1 protein on these cells is heavily glycosylated, and removal of N-glycosylation from PD-L1 disrupts the PD-1/PD-L1 interaction. Thus, a therapeutic approach that combines PD-L1 deglycosylation with effective antigen delivery may trigger a robust T cell-mediated antitumor immune response. In this study, we introduced an innovative synthetic approach to prepare hollow mesoporous silica nanoparticles with exceptionally large pores (H-XL-MSNPs) for efficient tumor cell lysate (TCL) encapsulation and delivery to antigen-presenting cells. The particles, with a ∼40 nm pore size, were loaded with TCL to activate DCs and further surface-modified with PNGase F to promote deglycosylation of N-linked sugar units on PD-L1. Treatment of MDA-MB-231 breast cancer cells, which exhibit high surface expression of PD-L1, with H-XL-MSNP-PNGase F significantly decreased their level of binding of recombinant PD-1. Pretreatment of MDA-MB-231 cells with H-XL-MSNP-PNGase F prior to coculturing with human T lymphocytes resulted in a significant activation of T cells and an increase in IL-2 secretion. When splenocytes from B16-sensitized tumor-bearing mice were cultured with H-XL-MSNP-TCL-treated DCs, an increase in CD69 expression and IL-2 production was observed. These findings indicate that H-XL-MSNPs can overcome some key limitations of current immunotherapies and may offer a promising alternative to antibody-based treatments by enhancing antigen presentation, disrupting PD-1/PD-L1 interactions, and eliciting robust antitumor T cell responses.