# Cell-penetrating peptide adaptors for intracellular cargo delivery

> **NIH NIH R15** · KENNESAW STATE UNIVERSITY · 2023 · $406,500

## Abstract

PROJECT SUMMARY
 Biomolecules that represent important therapeutic leads often fail because they cannot reach their targets,
commonly because of inability to cross cell membranes and reach appropriate subcellular destinations. Cell-
penetrating peptides (CPPs) have long held great promise for overcoming these failures. They are capable of
mediating penetration of the plasma membrane by molecules to which they are coupled, allowing delivery of
‘cargos’ to cell interiors, a potentially transformative platform technology that can enable an array of specific
applications. Nevertheless, development of CPP therapeutics has been disappointing because traditional CPP-
cargo molecules largely remain trapped in endosomes rather than reach the cytoplasm. The largest technical
hurdle to development of CPP therapeutics is failure to escape from endosomes – our technology solves this
problem. Our innovative approach is the use of high affinity but reversible noncovalent coupling to attach cargos
to CPPs. Our prototype CPP-adaptor fusion protein, TAT-Calmodulin (TAT-CaM), consists of the cell penetrating
moiety from HIV transactivator of transcription and human calmodulin. TAT-CaM binds CaM binding-site (CBS)
containing cargos with nM affinity in the presence of calcium but negligibly in its absence. Because mammalian
cells typically maintain low resting concentrations of calcium, cargos dissociate from the CPP-adaptor once
inside the cell, releasing cargo to the cytoplasm or other subcellular destination.
 This R15 AREA renewal application describes efforts to elucidate the mechanisms, kinetics and other basic
issues of CPP biology, engineer next-generation improvements in adaptors and cargos and develop methods to
use them to efficiently deliver cargos for research and therapeutic purposes. Success in these endeavors will
validate that our strategy is an adaptable tool for delivery of a wide array of macromolecules including nucleic
acids, potentially enabling the development of a new generation of innovative therapeutics and research tools.

## Key facts

- **NIH application ID:** 10653590
- **Project number:** 2R15EB028609-03A1
- **Recipient organization:** KENNESAW STATE UNIVERSITY
- **Principal Investigator:** JONATHAN L MCMURRY
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $406,500
- **Award type:** 2
- **Project period:** 2019-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653590

## Citation

> US National Institutes of Health, RePORTER application 10653590, Cell-penetrating peptide adaptors for intracellular cargo delivery (2R15EB028609-03A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10653590. Licensed CC0.

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