Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses

Abstract

Vaccines based on recombinant proteins avoid toxicity and anti-vector immunity associated with live vaccine (e.g., viral) vectors, but their immunogenicity is poor, particularly for CD8+ T-cell (CD8T) responses. Synthetic particles carrying antigens and adjuvant molecules have been developed to enhance subunit vaccines, but in general these materials have failed to elicit CD8T responses comparable to live vectors in preclinical animal models. Here, we describe interbilayer-crosslinked multilamellar vesicles (ICMVs) formed by crosslinking headgroups of adjacent lipid bilayers within multilamellar vesicles. ICMVs stably entrapped protein antigens in the vesicle core and lipid-based immunostimulatory molecules in the vesicle walls under extracellular conditions, but exhibited rapid release in the presence of endolysosomal lipases. We found that these antigen/adjuvant-carrying ICMVs form an extremely potent whole-protein vaccine, eliciting endogenous T-cell and antibody responses comparable to the strongest vaccine vectors. These materials should enable a range of subunit vaccines and provide new possibilities for protein therapeutic delivery.

Self-assembly of amphiphilic Janus dendrimers into uniform onion-like dendrimersomes with predictable size and number of bilayers

“…At 0.5 mg/mL the onion-like dendrimersomes exhibited narrow PDI with the size of about 200 nm in PBS and Hepes buffers. These are suitable dimensions for cell uptake and drug delivery (26,34,48). The preparation of onion-like dendrimersomes by direct injection Fig.…”

Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand T fh cells and promote germinal center induction

“…NPs may allow co-delivery of antigen and immunostimulatory molecules to the same intracellular compartment in antigenpresenting cells (APCs) (9) and promote cross-presentation of antigens, enhancing CD8 þ T-cell expansion and functionality (10)(11)(12). NP delivery of antigens and adjuvant molecules such as Toll-like receptor (TLR) agonists also has been shown to promote humoral immune responses (13,14).…”

“…We recently reported the design of a unique class of lipid-based NPs, interbilayer-crosslinked multilamellar vesicles (ICMVs), possessing many favorable characteristics for vaccine delivery (10). ICMVs, synthesized by forming covalent cross-links across lipid layers within multilayered lipid vesicles, are stable in the extracellular milieu following injection and retain entrapped proteins until the particles are internalized into intracellular compartments, thereby increasing the delivery of antigen to APCs in draining lymph nodes (dLNs).…”

Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment

“…The kinetics of antigen presentation were also shown to exert a major effect on the strength, [51]. Another considerable option to achieve longer-term antigen presentation by DCs is to use nucleic acid-based vaccines instead of protein or peptide vaccines.…”