Engineered Lipid Nanoparticles and Microgel Matrix to Program Th1/Th2 Immune Response

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY The overall objectives of this study are to (1) develop mRNA lipid nanoparticle (LNP) formulations capable of eliciting dual or biased Type 1 T helper (Th1) and/or Type 2 T helper (Th2) immune responses via a machine learning-aided screening platform, (2) engineer mRNA LNP- loaded microgels as an immunostimulatory niche in vivo to recruit and transfect host immune cells and potentiate antigen-specific immune responses, and (3) demonstrate the efficacy and safety of this new LNP-based vaccine platform in murine cancer models. The success of mRNA COVID-19 vaccines utilizing lipid nanoparticle (LNP) delivery has underscored the potential of mRNA LNP-based cancer vaccines in advancing immunotherapy by training the immune system to respond effectively to tumor antigens. To maximize their potency in eliciting robust immune responses for cancer immunotherapy, it is important to engineer effective approaches for systematic programming of immune activation profile via optimization of LNP compositions and improving delivery for mRNA LNP vaccines. Our preliminary data have demonstrated that LNP compositions and helper lipid structure influence the polarization of immune activation, and LNPs with dual Th1-plus-Th2 activation profile yielded the most potent antitumor efficacy in mouse tumor models. In addition, a candidate mRNA LNP vaccine loaded into a nanofiber-based microgel matrix, which facilitated recruitment and retention of host immune cells, enhanced antigen presentation, and elicited equally strong anti-tumor response with a single dose compared to a standard three-dose immunization regimen. In this proposed study, we will first optimize LNP composition for efficient transfection of antigen-encoding mRNA into antigen-presenting cells (APCs) and non-APCs via an machine learning-guided, iterative design-build-screen/test-learn process, and evaluate antigen presentation, and immune activation profiles in vivo; then develop an LNP-incorporated nanofiber microgel matrix termed LiNx as an immunostimulatory niche for recruitment of host immune cells and assess gene delivery efficiency and immune response profiles; and finally demonstrate the therapeutic efficacy and biosafety of the optimized LNPs and LiNx in suppressing tumor growth in therapeutic models of melanoma, lymphoma, and colon carcinoma in mice, as well as an orthotopic, immunoquiescent, pancreatic cancer mouse model. The innovation in this study lies in programming the immune activation profile generated by mRNA LNP vaccine by tunning cell-preferential transfection activity of LNPs and engineering an immunostimulatory niche using a nanofiber microgel matrix to recruit and retain host immune cells and deliver LNP vaccines, thus potentiating the therapeutic efficacy against cancer. Findings from this study can inspire rational design of new mRNA-based immunotherapies for the treatment of cancer and other diseases.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE This study aims to develop potent mRNA lipid nanoparticles (LNPs) with programmable Th1/Th2 immune activation profile, engineer a nanofiber microgel-based immunostimulatory niche to improve the delivery of LNP vaccines and boost the immune response, and evaluate their therapeutic efficacy in various mouse cancer models. Findings from this study will inspire the development of new mRNA LNP-based immunotherapies.