Nanomaterials‐Mediated Co‐Stimulation of Toll‐Like Receptors and CD40 for Antitumor Immunity

Abstract

Toll‐like receptors (TLRs) and CD40‐related signaling pathways represent critical bridges between innate and adaptive immune responses. Here, an immunotherapy regimen that enables co‐stimulation of TLR7/8‐ and CD40‐mediated pathways is developed. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, are synthesized and formulated into RAL‐derived lipid nanoparticles (RAL‐LNPs). The RAL2‐LNPs show efficient CD40 mRNA delivery to DCs both in vitro (90.8 ± 2.7%) and in vivo (61.3 ± 16.4%). When combined with agonistic anti‐CD40 antibody, this approach can produce effective antitumor activities in mouse melanoma tumor models, thereby suppressing tumor growth, prolonging mouse survival, and establishing antitumor memory immunity. Overall, RAL2‐LNPs provide a novel platform toward cancer immunotherapy by integrating innate and adaptive immunity.

Small-Molecule Modulators Targeting Toll-like Receptors for Potential Anticancer Therapeutics

“…Nanomaterials have been widely used in cancer therapy in recent years. Lipid nanoparticles (RAL-LNPs) derived from TLR7 and TLR8 agonist R-848 can be used to deliver CD40 mRNA (RAL CD40-LNPs), thereby stimulating TLR7 and TLR8 and CD40-mediated pathways simultaneously, resulting in effective antitumor activity in mouse melanoma models . This approach provides a new platform for cancer immunotherapy.…”

“…Lipid nanoparticles (RAL-LNPs) derived from TLR7 and TLR8 agonist R-848 can be used to deliver CD40 mRNA (RAL CD40-LNPs), thereby stimulating TLR7 and TLR8 and CD40-mediated pathways simultaneously, resulting in effective antitumor activity in mouse melanoma models. 189 This approach provides a new platform for cancer immunotherapy. In summary, small-molecule modulators that target TLRs have great potential as antitumor agents.…”

Vaccination of TLR7/8 Agonist‐Conjugated Antigen Nanoparticles for Cancer Immunotherapy

“…[ 13 ] To address this issue, it is highly desirable to provide a local TLR activation to restrict the systemic exposure of the agonists. [ 14 ]…”

STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2

“…4-R 1 has three linear carbon tails. As the geometrical shape of an ionizable lipid can affect its self-assembled structure of the LNPs, which is a key factor governing its endosomal escape function, , we incorporated linear or branched biodegradable tails in 4-R 2 to 4-R 7 to alter their chemical space. 4-R 2 contains an ester group, 4-R 3 to 4-R 5 contains a carbonates group, and 4-R 6 and 4-R 7 contain an acid-labile acetal group.…”

“…Among them, messenger RNA (mRNA)-based vaccines represent a fast-evolving biomacromolecule because of their rapid speed in development, large-scale manufacture, and safe administration . Among various platforms for nucleic acid delivery, lipid nanoparticles (LNPs)-mRNA formulations have been comprehensively investigated for the treatment of cancer, − genetic disorders, − and infectious diseases. − Currently, the FDA has approved two mRNA SARS-CoV-2 vaccines delivered via lipid nanoparticles, namely, BNT162b2 and mRNA-1273, marking a milestone for the adoption of LNP-mRNA therapeutics. Despite the two SARS-CoV-2 vaccines eliciting a robust immune response, the emergence of new SARS-CoV-2 variants undermines the protective efficacy of antibody neutralization in infected and vaccinated individuals .…”