# Development of Anti-Fouling Peptide-Nanoparticle Conjugates for the Delivery of siRNA to Fractures

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2020 · $45,520

## Abstract

Small interfering RNA (siRNA) are a promising class of drugs that are limited by delivery challenges. Naked
siRNA has poor cellular uptake and rapid degradation in vivo, thus siRNA is typically administered in
nanoparticle (NP) formulations. To circumvent extracellular barriers of degradation and poor uptake as well as
intracellular lysosomal trafficking, our lab pioneered the development of pH-responsive cationic diblock
tercopolymer nanoparticles (pHCNPs) for the delivery of siRNA, which greatly improve siRNA therapeutic
efficacy. Local in vivo delivery of siRNA-pHCNPs has shown promise in bone and other tissues, but many
diseases, including many of the musculoskeletal system require systemic administration. Systemic delivery of
NPs is hampered due to serum adsorption, leading to mononuclear phagocyte system (MPS) uptake and poor
circulation times, and may potentiate immunogenicity. In fact, many siRNA-NP therapeutics that are approved
or in late stages of development take advantage of MPS accumulation in liver, targeting hepatic diseases.
Reducing protein-NP interactions is key to improving the systemic delivery of siRNA-NPs to reach other target
tissues. Poly(ethylene glycol) (PEG) modification (PEGylation) of NPs is the current standard to reduce protein
adsorption, but it also reduces NP efficacy by hampering uptake and may induce immunological responses
due to anti-PEG antibodies. Zwitterionic (ZI) moieties have shown great promise in reducing protein adsorption
and are less disruptive to NP functional characteristics than PEG. Biomimetic ZI peptides (ZIPs) are a
promising new approach to improve polymeric NP pharmacokinetic properties. In particular, semi-randomized
ZIPs (srZIPs) allow testing of charge sequence semi-independently of amino acid composition. These
attributes altogether lead to the hypothesis that semi-randomized ZIPs (srZIPs) designed with low
aggregation potential can be used to modify NPs to improve systemic circulation and siRNA delivery
by reducing NP-serum protein interactions. We will test this hypothesis in three ways. In Aim 1, we will
generate a library of srZIP-pHCNP conjugates to test the effects on serum-induced aggregation compared to
naïve pHCNPs and PEG-pHCNPs. In Aim 2A, we will test these conjugates in vitro using target cells
(mesenchymal stem cells) and in MPS cells (macrophages), and in Aim 2B we will evaluate improvements in
circulation times of the pHCNP conjugates in vivo. In Aim 3 we will use an established mouse femur fracture
model to investigate fracture accumulation of pHCNP bearing therapeutic anti-WWP1 siRNA (WW Domain
Containing E3 Ubiquitin Protein Ligase 1, a negative regulator of fracture healing), which we have shown to
expedite bone fracture healing in using a local delivery approach. At the completion of this project, we expect
to identify new peptide-based anti-aggregation approaches for the delivery of siRNA in polymeric
nanoparticles, laying the foundation for future systemic deliver...

## Key facts

- **NIH application ID:** 9907178
- **Project number:** 1F31AR076874-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Clyde Thomas Overby
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907178

## Citation

> US National Institutes of Health, RePORTER application 9907178, Development of Anti-Fouling Peptide-Nanoparticle Conjugates for the Delivery of siRNA to Fractures (1F31AR076874-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9907178. Licensed CC0.

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