# Controlling complement to unleash nanomedicine for acute critical illnesses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $626,215

## Abstract

ABSTRACT / SUMMARY
 Acute critical illnesses rapidly lead to severe organ damage and loss of life. These illnesses include
sepsis, stroke, and acute respiratory distress syndrome (ARDS). Here we focus on ARDS, which is acute
inflammation of the lungs’ air sacs, and the cause of death in COVID-19. For ARDS and these other diseases,
we have developed ligand-targeted nanocarriers that localize drugs to the inflamed microvasculature of affected
organs. As we moved towards clinical translation, we found the key step is gaining control of complement, a set
of plasma proteins that bind microbes and aid their clearance. But we found complement-nanoparticle
interactions are a “double-edged sword”, with both benefits to optimize, and deleterious features to resolve.
 First, we found that complement protein C3 rapidly opsonizes particular nanoparticles, and that such C3-
opsonized nanoparticles then act as “decoys” to ameliorate ARDS mouse models (e.g., nebulized LPS) by ~75%.
The C3-coated nanoparticles accumulate in marginated leukocytes, which are key to ARDS pathophysiology,
and cause those cells to leave the lungs. However, C3 opsonization induces an anaphylaxis-like reaction called
CARPA (complement-activation-related pseudo-allergy). Therefore, in Aim 1, we will engineer nanoparticles
that can function like C3-coated decoys to ameliorate ARDS, but without CARPA. We will also investigate the
mechanism underlying nanoparticle decoy therapy. Then we will test the translational potential of these
optimized decoy nanoparticles by testing them in fresh, perfused, ex vivo human lungs.
 Second, we found that the ligand-targeted nanoparticles we have been developing for drug delivery for
years also induce CARPA. Therefore, in Aim 2, we will re-engineer our ligand-targeted nanoparticles to prevent
CARPA. We will test a drug carrier we have previously used to concentrate drugs in the alveolar
microvasculature of the lungs: liposomes conjugated to anti-PECAM antibodies that bind endothelial cells. We
will test in vitro and in vivo in mice whether various engineered versions of anti-PECAM liposomes can evade
C3 opsonization and CARPA, and thereby achieve more specific delivery to the lungs. Lastly, we will test these
CARPA-avoiding nanoparticles with plasma from ARDS patients, as such patients have perturbed complement.
 Upon completion of these two Aims, we will have developed two technologies that may aid therapy of
ARDS: 1) Decoy nanoparticles that safely cause marginated leukocytes to leave the lungs, and thereby
ameliorate ARDS-like phenotypes; 2) A technology for preventing complement side effects such as CARPA
when delivering ligand-targeted nanoparticles. As marginated leukocytes play pivotal roles in most acute critical
illnesses, and CARPA sensitivity is common to those as well, the technologies developed here may impact not
only ARDS, but also sepsis, stroke, and more.

## Key facts

- **NIH application ID:** 10340537
- **Project number:** 1R01HL160694-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jacob Brenner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $626,215
- **Award type:** 1
- **Project period:** 2022-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10340537

## Citation

> US National Institutes of Health, RePORTER application 10340537, Controlling complement to unleash nanomedicine for acute critical illnesses (1R01HL160694-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10340537. Licensed CC0.

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