# The Alternative Complement Pathway and Hemocompatibility of Nanosurfaces

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $491,764

## Abstract

Project Abstract
Intravenously injected nanoparticulate drugs are cleared by phagocytes and elicit immune reactions,
including cytokine release and pseudoallergy (up to 10% in Doxil® and 30% in Onpattro®). There is
substantial preclinical evidence on the involvement of the serum complement system in these
responses. Understanding the mechanisms of complement activation in patients and designing
preventive strategies can improve the safety and efficiency of nanoparticle-based drugs. We found
that cell membrane-derived inhibitors of complement can effectively shut off complement activation
and prevent the uptake of nanoparticles by leukocytes in the blood of healthy donors. Furthermore,
the inhibitors that are designed to target complement deposits on the nanoparticle surface showed
picomolar activity, for all nanoformulations we tested. The available data suggest a novel hypothesis
wherein less than 1% of nanoparticles act as initiators of the complement cascade. Our long-term
goal is to conduct a clinical trial of combination of nanomedicines with complement inhibitors. Such a
trial will provide the nanomedicine field with the ultimate answers on the role of complement in
hemocompatibility, clearance, and infusion reactions in humans. The main objectives of this proposal
are 1) to further understand mechanisms of complement initiation by nanoparticles; 2) to design a
rapid companion test to measure complement activation by nanoparticle-based drugs; 3) to study the
efficacy of nanoparticle-binding inhibitors in blood of defined cohorts of patients in vitro and in dogs.
This research will shift the existing paradigm of stealth design: it will enable the control and fine-
tuning of the biocompatibility of nano-sized drug delivery and imaging systems using specific
inhibitors.

## Key facts

- **NIH application ID:** 10053157
- **Project number:** 9R01AI154959-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Dmitri Simberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,764
- **Award type:** 9
- **Project period:** 2016-06-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053157

## Citation

> US National Institutes of Health, RePORTER application 10053157, The Alternative Complement Pathway and Hemocompatibility of Nanosurfaces (9R01AI154959-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10053157. Licensed CC0.

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