Adjuvants for cancer mRNA vaccines in the era of nanotechnology: strategies, applications, and future directions

Abstract

Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS.

Keywords: Adjuvant; Drug delivery system; Nanotechnology; mRNA cancer vaccine.

Fig. 1

“WESP”-the key advantages of mRNA vaccines. The remarkable success of mRNA vaccines can be attributed to several key advantages which can be summarized by the acronym “WESP”: “W”: Wide applicability, “E”: Efficiency, “S”: Safety, “P”: Productiveness

Fig. 2

The design strategies for immunostimulants. Various types of immunostimulants activate different PRRs, leading to the secretion of various cytokines and inducing diverse adaptive immune responses. Immunostimulants activate TLRs, cGAS-STING, CLRs, other PRRs, or directly release cytokines to induce and modulate adaptive immune responses. Binding to TLRs heterodimers initiates MyD88 pathway and activated NF-κB and ERK1/2 to enhance pro-inflammatory cytokines. The mtDNA and dsDNA initiates the conversion of cGAS into cGAMP and consequently activates STING to release TBK to activates IRF 3 and IKKi to activates NF-κB. Finally, IRF 3 induces type 1 interferons, cross presentation and CTL and NF-κB induces pro-inflammatory cytokines and activate Th1 cells. Targeting to most CLRs activated NF-κB to enhance pro-inflammatory cytokines. Notably, targeting to CD205 and CD206 can enhance endocytosis and antigen presentation. Common immunostimulants targeting to NLRs (NOD 1 and NOD 2) activated NF-κB ultimately produces a predominantly Th2-type of immune response. Alternatively, immunostimulants targeting to MDA5 and RIG-I activate IRF 3 and IRF 7 respectively. At length, IRF 3 and IRF 7 induce type 1 interferons, cross presentation, CTL and activate Th1 cells

Fig. 3

The design strategies for self-adjuvant drug delivery systems. Self-adjuvant delivery systems increased antigen presentation to enhance adaptive immune responses by enhancing the bioavailability of antigens; targeting immune organs or cells; promoting antigen cross-presentation; and activating inflammasome. Enhancing the bioavailability of antigens can be achieved by sustained releasing antigens, formatting immune niches, and protecting antigens from breakdown. Targeting APCs can be achieved by using nanoscale materials, constructing highly ordered and repetitive spatial structures to mimic pathogens and targeting specific receptors on APCs. Targeting lymph node can achieved through the design of suitable dimensions (20 to 200 nm), surface properties (negative charge and hydrophobicity) and albumin-hitchhiking. Promoting antigen cross-presentation can be enabled in three main ways, proton sponge effect, destabilization of membranes and photochemical internalization

Fig. 4

The deficiencies of mRNA adjuvants and the prospects for improvement. The immune-related adverse event, unsatisfactory outcomes in old age group and unclear mechanism of adjuvants are three main deficiencies of the mRNA adjuvants. Alternatively, optimizing drug delivery systems, improving route of administration and further explored the mechanisms of adjuvant are three main prospects for the improvement of mRNA adjuvants