# Mechanisms of Nanomaterials-based Combination Adjuvants

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $498,707

## Abstract

PROJECT SUMMARY
The discovery of pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and NOD-like
receptors (NLRs) has led to the investigation of molecular agonists of innate immunity in adjuvant formulations.
An emerging paradigm is that careful selection of adjuvant combinations can result in complementary and even
synergistic enhancement of vaccine-induced immune responses. Most combination adjuvants under
investigation are chemically heterogeneous mixtures of depot adjuvants mixed with PRR agonists and suffer
from batch-to-batch variability and poor chemical definition making investigation of mechanisms and safety a
challenge. Our lab investigates self-assembling peptide nanofibers (PNFs) as vaccine adjuvants. A key
advantage of PNFs over emulsion adjuvants is that the primary sequence of the self-associating peptide can be
designed to control the physicochemical features of PNFs such as morphology, charge, chirality, or
hydrophobicity, which are key contributors to adjuvant activity. Mechanistic insights into the mode of action
indicates that unlike PAMPs, PNFs do not cause DC maturation but facilitate the release of DAMPs related to
osmotic/oxidative stress. In this application, we propose to develop combination adjuvants composed of
chemically defined DAMP-inducing peptide nanofibers (PNFs) and TLR2/NOD2 agonists.
Our objectives are to understand how molecular mechanisms of DAMP-inducing PNFs and PRR agonists
orchestrate innate immune signaling and induce responses that are complimentary, synergistic, or inhibitory for
balancing immunogenicity with safety. In aim 1, we will examine the effect of PNFs with varying physicochemical
properties and TLR2 or NOD2 agonist combinations on DC activation, DAMP release, and antigen presentation.
In aim 2, using a design of experiments (DOE) approach, we will develop an optimal formulation with precisely
controlled PNF-TLR2 and PNF-NOD2 combinations and determine the molecular mechanisms of innate
immunity in DCs using various KO mouse models. In aim 3, we will validate the efficacy of PNF-TLR2-NOD2
combination adjuvants and investigate translational potential using human DCs.
Outcomes of the proposed studies will advance our understanding of the molecular mechanisms that mediate
innate immune responses to PNF-PRR agonist adjuvant combinations and will lead to new combinatorial-
adjuvant platforms for combating infectious and non-infectious diseases with high translational potential.

## Key facts

- **NIH application ID:** 10748389
- **Project number:** 5R01AI168918-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jai Rudra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $498,707
- **Award type:** 5
- **Project period:** 2022-12-05 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10748389

## Citation

> US National Institutes of Health, RePORTER application 10748389, Mechanisms of Nanomaterials-based Combination Adjuvants (5R01AI168918-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10748389. Licensed CC0.

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