# Heteromutivalent Peptide-Lipid Nanoconstructs as Artificial Platelet Analogues

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $563,243

## Abstract

Platelets play a central role in hemostasis via injury site-selective multi-step mechanisms of: (1) Adhesion to vWF
and collagen, (2) Fibrinogen-mediated aggregation to form the primary hemostatic plug, (3) Biointerfacial
presentation of anionic phosphatidylserine (PS) on the activated platelet surface for procoagulant amplification
of thrombin (hence fibrin), and (4) clot-localized secretion of platelet granule contents (e.g. inorganic
polyphosphate, PolyP) to locally enhance fibrin stability. These mechanisms are significantly compromised in
non-compressible traumatic hemorrhage, which remains a major cause of mortality. The `gold standard' for
treating such hemorrhage is massive transfusion of whole blood or components (platelets, plasma, RBC).
Especially, platelet transfusion has shown tremendous clinical benefit in saving lives in trauma. However,
platelets are rarely available in resource-limited hospitals and unavailable pre-hospital, due to challenges of
storage, portability, high risk of bacterial contamination and very short shelf-life (~5 days). We aim at addressing
this challenge by designing biomaterials-based `artificial platelet' nanoconstructs. To this end, utilizing a
previous R01 award (HL121212) we developed self-assembled lipid-peptide nanoconstructs that mimic and
integrate the platelet mechanisms of (1) and (2) stated above. This design showed hemostatic ability in vitro and
in thrombocytopenic mouse tail-bleeding models, and modest efficacy in severe trauma models. Building on this,
we now propose to mimic the mechanisms of (3) and (4) on a liposomal template by designing unique enzyme-
responsive lipopeptides, that will subsequently allow integration of all four mechanisms onto a single
nanoconstruct for a superior artificial platelet design. Our central hypothesis is `Modular amplification of
hemostasis via mimicry of platelet's biointerfacial and secretory mechanisms within an artificial platelet
construct can significantly attenuate hemorrhage and enhance survival in trauma'. To test this, our Specific Aims
are to: (1) Evaluate stimuli (plasmin)-triggered exposure of PS on lipidic nanoconstructs for platelet-inspired
amplification of thrombin (hence fibrin) site-specifically in trauma; (2) Evaluate stimuli (thrombin)-triggered
release of inorganic polyphosphate (PolyP) as a payload from lipidic nanoconstructs for injury site-targeted
stabilization of fibrin clot; and (3) Integrate these independent synergistic components in artificial platelet
nanoconstructs to evaluate hemostatic efficacy and survival in rodent trauma model. The traumatic insult to
vascular endothelium results in enhanced secretion of tissue plasminogen activator (hence plasmin) at the clot
site, resulting in rapid fibrin degradation (hyperfibrinolysis) and compromising clot stability. Exploiting this
plasmin to expose PS on `artificial platelet' surface will allow enhanced thrombin (and hence fibrin) generation
to offset hyperfibrinolysis. This thromb...

## Key facts

- **NIH application ID:** 10122280
- **Project number:** 2R01HL121212-06A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Anirban Sen Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $563,243
- **Award type:** 2
- **Project period:** 2014-02-08 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122280

## Citation

> US National Institutes of Health, RePORTER application 10122280, Heteromutivalent Peptide-Lipid Nanoconstructs as Artificial Platelet Analogues (2R01HL121212-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10122280. Licensed CC0.

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