# Kinetic Assembly of Polymer-mRNA Nanoparticles Targets Circulating Monocytes to Enhance Cancer Immunotherapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $538,330

## Abstract

PROJECT SUMMARY
Cancer vaccines have significantly advanced cancer immunotherapy; and recent successes of mRNA
vaccines have raised prospect of generating potent anti-tumor response by specifically delivering mRNAs
encoding tumor-associated antigens to antigen presenting cells (APCs). However, APC activation elicited by
nanoparticles containing antigen mRNAs is rather limited. Circulating monocytes offer a promising cell target as
an abundant APC precursor that can be deposited to spleen, lymph nodes, and tumor tissue following
polarization and activation. The overall objective of this study is to engineer
kinetically assembled poly(beta-
amino ester) (PBAE)
/mRNA nanoparticles (KaNPs) that can specifically deliver mRNAs encoding tumor antigens
and immunoadjuvants into circulating monocytes in vivo and demonstrate the safety and efficacy of this new
mRNA cancer vaccine platform. This study is built on the preliminary results showing biodegradable
PBAE/mRNA KaNPs with an optimized size of 400 nm mediated preferential transfection of circulating
monocytes following intravenous (i.v.) injection, leading to more effective transfection and deposition of
circulating monocytes and a higher level of tumor-killing activity compared to the standard small size
PBAE/mRNA nanoparticles. In this proposed study, we plan to pursue four specific aims: (1) optimize the
composition, size, and surface functionality of PBAE/mRNA KaNPs to improve targeted mRNA delivery efficiency
into circulating monocytes in vivo, (2) characterize pharmacokinetic profile of PBAE/mRNA KaNPs and define
functions of transfected circulating monocytes in vivo, (3) assess the immunotherapeutic efficacy of PBAE/mRNA
KaNPs in suppressing tumor growth in combination with TLR9 and STING agonists in mouse tumor models, and
(4) develop an GMP-compliant, shelf-stable, lyophilized PBAE/mRNA KaNP formulation and validate the efficacy
in a mouse model. If successful, this study will uncover structure-function relationships in a previously
inaccessible size range (200–1000 nm) for gene therapy carriers, demonstrate circulating monocytes as a potent
mRNA therapeutic target and the role of KaNP-transfected circulating monocytes in potentiating antitumor
immune responses, and inspire rational design of new mRNA-based immunotherapies for treatment of solid
tumors and metastatic cancers.

## Key facts

- **NIH application ID:** 10846665
- **Project number:** 5R01CA281143-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jordan Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $538,330
- **Award type:** 5
- **Project period:** 2023-05-23 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846665

## Citation

> US National Institutes of Health, RePORTER application 10846665, Kinetic Assembly of Polymer-mRNA Nanoparticles Targets Circulating Monocytes to Enhance Cancer Immunotherapy (5R01CA281143-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846665. Licensed CC0.

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