Development of a Cancer Nanovaccine to Induce Antigen-specific Immune Responses Based on Large-Sized Porous Silica Nanoparticles

Abstract

Cancer vaccine is one of the immunotherapeutic strategies aiming to effectively deliver cancer antigens to professional antigen-presenting cells such as dendritic cells (DCs), macrophages, and B cells to elicit a cancer-specific immune response. Despite the advantages of the cancer vaccine that can be applied to various cancer types, the clinical approach is limited due to the non-specific or adverse immune responses, stability, and safety issues. In this study, we report an injectable nanovaccine platform based on large-sized (∼350 nm) porous silica nanoparticles (PSNs). We found that large-sized PSNs, called PS3, facilitated the formation of an antigen supply depot at the site of injection so that a single injection of PSN-based nanovaccine elicited sufficient tumor-specific cell-mediated and humoral immune response. As a result, antigen-loaded PS3 induced successful tumor regression in prophylactic and therapeutic vaccination.

Enhanced Local Delivery of Engineered IL-2 mRNA by Porous Silica Nanoparticles to Promote Effective Antitumor Immunity

“…To enhance mRNA delivery efficiency while minimizing systemic biodistribution, we developed large-sized rigid nanoparticles, L-PPSNs. To prepare L-PPSNs, we first synthesized large-sized bare PSNs following our previous report with a slight modification. , The synthesis involved the use of cetyltrimethylammonium bromide (CTAB) as a template to create a porous structure and tetramethyl orthosilicate (TMOS) as the silica precursor. Subsequently, we applied PEI (1.8 kDa) through electrostatic interaction to facilitate the mRNA loading and delivery .…”

“…Nanoparticles were received from Lemonex Inc. L-PPSNs were synthesized according to the previously published method with slight modification. , In brief, CTAB and 1 M NaOH solution were dissolved in methanol/water (0.6/0.4 = w/w). With vigorous stirring, TMOS was added under ambient conditions, and the mixture was aged overnight after 8 h of stirring.…”

“…Recently, we have investigated the use of PSNs for antigen delivery and demonstrated the ability to induce a scaffold structure at the injection site, as well as sustained release of antigen upon subcutaneous injection. 33 These results suggest that PSNs have the potential to be a versatile platform for drug delivery.…”

“…Porous silica nanoparticles (PSNs) have emerged as promising drug delivery vehicles due to their tunable physicochemical properties, such as particle size, pore size, pore structure, and surface functionality. ,, In our previous studies, we demonstrated the highly efficient delivery of siRNA and Cas9 ribonucleoprotein (RNP) using PSNs, with a sustained release profile. Recently, we have investigated the use of PSNs for antigen delivery and demonstrated the ability to induce a scaffold structure at the injection site, as well as sustained release of antigen upon subcutaneous injection . These results suggest that PSNs have the potential to be a versatile platform for drug delivery.…”

Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy

“…PSN is an appropriate vehicle for carrying KYNase mainly due to its flexible surface chemistry, pore size control, and biocompatibility . Furthermore, PSNs can be degraded into oligomers or monomers in the body fluid and excreted through renal clearance. , In the previous study from our group, the protein-loaded PSNs showed an increased retention time in the TME compared to free protein. , Inspired by the result, we designed a type of PSN suitable for carrying KYNase, named ‘BALL’ First, the pore size of BALL was chosen at ∼12 nm to load KYNase, whose hydrodynamic size is known to be around 9 nm . Next, the pore surface of BALL was designed to present a positive charge under physiological conditions, leading to an electrostatically attractive interaction with KYNase, whose isoelectric point is smaller than 7.0.…”