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.