# Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles

> **NIH NIH P20** · UNIVERSITY OF MISSISSIPPI · 2021 · $251,567

## Abstract

Project 4: Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles
Junior Investigator: Thomas Werfel
Mentor: Adam Smith, University of Mississippi
Efferocytosis, the phagocytic clearance of apoptotic cells, in the tumor microenvironment promotes
immunosuppression, dampening anti-tumor immunity and thus the therapeutic response to cytotoxic and
immunotherapies. Macrophages are primarily responsible for efferocytosis in the tumor microenvironment, where
they recognize apoptotic cells using the phosphatidylserine receptor MerTK and then produce a host of
immunosuppressive signals in response to apoptotic cell engulfment. Attempts to block efferocytosis in the tumor
microenvironment by inhibiting the activity of MerTK show promise. However, chronic, systemic blockade of
MerTK and/or hypomorphic MerTK mutations contribute to inflammation-related retinopathies, lupus-like auto-
immunity, and risk of auto-immunity. To circumvent the deleterious effects of auto-immunity associated with
chronic systemic inhibition, we propose to target MerTK specifically within tumor-associated macrophages
(TAMs) using high-mannose decorated-nanoparticles (hmn-NPs) harboring a MerTK inhibitor. We propose novel
synthetic strategies to produce nanoparticles with 1) a polypropylene sulfide core for hydrophobic drug loading
and targeted release and 2) a glycopolymer-based corona consisting of a mixture of trehalose and mannose
polymers. Trehalose has been shown to impart enhanced stability to drug delivery vehicles and will be crucial
for endowing the stability necessary for systemic delivery applications. Mannose has been used to target
nanoparticles to TAMs because of their characteristic overexpression of the mannose receptor. However, past
strategies have been limited to local delivery applications and have employed monomeric versions of mannose.
Our polymeric version of mannose will more closely mimic the natural binding partners for mannose receptor,
mannan and high-mannose glycans, which have much higher affinity than monomeric mannose. Thus, a major
goal of this project is to rigorously compare the effectiveness of monomeric mannose and polymannose as
targeting strategies for TAMs. Using the TAM-targeting hmn-NPs as an enabling technology, we will test the
therapeutic impact of TAM-specific MerTK inhibition on immunosuppression in the tumor microenvironment,
tumor progression, and systemic auto-immunity.

## Key facts

- **NIH application ID:** 10165752
- **Project number:** 5P20GM130460-02
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI
- **Principal Investigator:** Thomas A Werfel
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,567
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165752

## Citation

> US National Institutes of Health, RePORTER application 10165752, Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles (5P20GM130460-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165752. Licensed CC0.

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