# Vascular delivery of nanocarriers by erythrocyres

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $705,544

## Abstract

Project Summary
The multifunctional endothelial interface between blood and tissues is an important target for
therapeutic interventions in many human maladies. To achieve precise interventions, many labs
including us conjugate drugs and drug carriers with affinity ligands that target cargoes to the
endothelium. On the other hand, carriers that accumulate in tissues via non-affinity mechanisms may
provide an additional boost in drug delivery capacity. We have found that reversible association of
nanocarriers (NCs) with the red blood cell (RBC) surface provides a new strategy combining targeted
and non-targeted approaches. NCs adsorbed onto isolated RBCs (RBC/NC) rapidly transfer to the
vasculature downstream of the injection site and avoid hepatic uptake. Pilot data show that we can
synergize the power of RBC-hitchhiking and affinity targeting. Loading on RBCs provides almost
three orders of magnitude boost of uptake of EC-targeted NCs in the lungs. Further, RBC-targeted
NCs safely load onto RBCs in vivo, which allows us to avoid transfusion. To combine these
advantages and enable transfer from RBCs to ECs, we have designed dual-targeted NCs (DTNCs)
by conjugating to opposite facets of anisotropic “Janus” particles ligands that bind to RBCs and EC.
Fine-tuning of each facet's avidity maximizes spatiotemporal control of targeting to RBCs and transfer
to ECs. We identified ligands selectively targeting NCs to the brain vs lungs. The goal of this proposal
is to define the mechanism and enable translation of this novel, paradigm-shifting strategy. We will
employ mutually reinforcing models: in vitro (microfluidic), ex vivo (perfused human lungs) and in vivo
(naïve vs pathological animals). We will study NC loading onto RBC and the transfer to and
localization in recipient cells, and the effect of drug delivery by RBC-hitchhiking in three independent
Aims. Aim 1: Loading NC onto RBCs. We will: A) Define optimal NC design for RBC loading; B)
Engineer RBC-targeted NC loading in vivo; and, C) Determine the biocompatibility of NC-loaded
RBCs. Aim 2: NC unloading and transfer. We will characterize and optimize vascular transfer of
untargeted NCs vs EC-targeted and dual-targeted NCs: A) Kinetics and amplitude of transfer; B)
Cellular addressing and trafficking of NCs; and, C) Pathophysiological factors modulating transfer.
Aim 3: Translational RBC hitchhiking. We will: A) Appraise beneficial vs unintended effects of
delivery of anti-inflammatory agents by RBC/NC; B) Refine NC targeting to human RBC; and, C)
Recapitulate key findings of animal studies in perfused human lungs. This study will advance: A)
Design of drug delivery systems combining targeted nanocarriers with “supercarrier” RBCs; B)
Understanding of important vascular interfaces; C) Development of precisely targeted
pharmacotherapy for treatment of ALI/ARDS and likely stroke and other common acute crises.

## Key facts

- **NIH application ID:** 9922385
- **Project number:** 5R01HL143806-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vladimir R Muzykantov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $705,544
- **Award type:** 5
- **Project period:** 2018-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922385

## Citation

> US National Institutes of Health, RePORTER application 9922385, Vascular delivery of nanocarriers by erythrocyres (5R01HL143806-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922385. Licensed CC0.

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