Lipidation Approaches Potentiate Adjuvant-Pulsed Immune Surveillance: A Design Rationale for Cancer Nanovaccine

Abstract

Adjuvant-pulsed peptide vaccines hold great promise for the prevention and treatment of different diseases including cancer. However, it has been difficult to maximize vaccine efficacy due to numerous obstacles including the unfavorable tolerability profile of adjuvants, instability of peptide antigens, limited cellular uptake, and fast diffusion from the injection site, as well as systemic adverse effects. Here we describe a robust lipidation approach for effective nanoparticle co-delivery of low-molecular weight immunomodulators (TLR7/8 agonists) and peptides (SIINFEKL) with a potent in vivo prophylactic effect. The lipidation approaches (C 16-R848 and C 16-SIINFEKL) increased their hydrophobicity that is intended not only to improve drug encapsulation efficiency but also to facilitate the membrane association, intracellular trafficking, and subcellular localization. The polymer-lipid hybrid nanoparticles (PLNs) are designed to sustain antigen/adjuvant levels with less systemic exposure. Our results demonstrated that a lipidated nanovaccine can induce effective immunity by enhancing the expansion and activation of antigen-specific CD8 + T cells. This adaptive immune response led to substantial tumor suppression with improved overall survival in a prophylactic setting. Our new methodology enhances the potential of nanovaccines for anti-tumor therapy.

Targeted Repolarization of Tumor‐Associated Macrophages via Imidazoquinoline‐Linked Nanobodies

“…[ 36 ] To circumvent these limitations, new technologies have been used as delivery systems of TLR7/8 ligands, including lipidation approaches, encapsulating nanoparticles, adsorption to aluminum salts adjuvants, and conjugation to polymers. [ 35–37,42,55–57 ] Nevertheless, these formulations cannot be considered as specific TAM‐targeted therapies. For instance, the uptake of IMDQ‐encapsulated nanoparticles was also mediated by DCs, monocytes, and B cells [ 42 ] and their anti‐tumoral effect seem to be largely DC‐driven.…”

Understanding Structure–Function Relationships of Nanoadjuvants for Enhanced Cancer Vaccine Efficacy

“…[ 154 ] Shi's group prepared a lipophilized nanoadjuvant by combining core‐shell polymer‐lipid hybrid nanoparticles (PLN) with low molecular weight lipophilic molecules. [ 155 ] This nanoadjuvant minimizes systemic exposure, enhances the loading efficiency of proteins or agonists such as TLR7/8 agonists and peptides (SIINFEKL), increases its uptake by APCs, and prolongates immune memory effects, making it a promising material for cancer treatment or prevention. In addition, they also prepared adjuvant pulsed mRNA vaccine nanoparticles coated with a lipid polyethylene glycol (lipid‐PEG) shell, which consisted of ovalbumin‐encoded mRNA and palmitic acid‐modified TLR7/8 agonist R848 (C 16 ‐R848).…”

Vaccine adjuvant platform and fluorescence imaging of amphiphilic γ-PGA-IMQ-LA-FL conjugates

“…23,24 The structure of liposomes allows them to interact with various cells and components of the immune system, rendering them ideal candidates for antigen delivery. [25][26][27] The conjugation of a small molecule TLR7 agonist to macromolecular constructs provides the possibility to impede systemic clearance, positively affecting the pharmacokinetic profiles. 28,29 In addition, lipid amphiphiles exhibit an affinity to albumin and lipoproteins and hence promote lymphatic translocation to lymphoid tissues by ''hitching a ride'' along the interstitial albumin flow.…”