# Development of NAD+ loaded nanoparticles as a safe and efficient strategy to combat sepsis.

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $194,375

## Abstract

Project Summary
Sepsis is a complex disorder caused by a dysregulated host response to infection. Current sepsis therapeutic
strategies do not adequately address immune dysregulation and endothelial dysfunction. NAD+ can potentially
be an efficient therapeutic molecule for sepsis, but its therapeutic efficacy is hindered by its inability to pass
through the cell membrane. Extracellular NAD+ has to be degraded into NAD+ precursors (e.g., nicotinamide and
nicotinamide riboside), which can be taken up by cells and subsequently enhance intracellular NAD+ biosynthesis.
However, this conversion process is inefficient. Such a limitation in NAD+ intracellular transportation drastically
decreases the bioactivity of NAD+ and necessitates an extremely high dose for effective therapy.
We aim to develop an innovative, safe, and effective sepsis therapy utilizing NAD+ delivery nanoparticles (NPs),
which can directly (i.e., without being converted to NAD+ precursors) and efficiently replenish the cellular NAD+
pool, in combination with a broad-spectrum antibiotic. To achieve this goal, we formulated a family of NAD+ or
NAD+/antibiotic (e.g., rifampicin (Rif)) loaded lipid (LP)-coated calcium phosphate nanoparticles (NPs) (coined
as NAD+ loaded NPs including NAD+-LP-CaP and NAD+-Rif-LP-CaP). The NAD+ loaded NPs possess a number
of desirable properties including high loading content, high stability, pH-responsive drug release profiles, and
endosomal escape capability. Despite the therapeutic potential of NAD+, there is no prior report on in vivo studies
using NAD+ NPs for therapeutic studies including sepsis. Our preliminary data has demonstrated that NAD+-LP-
CaP can suppress the release of pro-inflammatory cytokines and prevent inflammation-induced cell death and
endothelium disruption. Therefore, NAD+ loaded NPs can potentially help maintain homeostasis of both the
immune system and the vascular system. Our NAD+ loaded NPs successfully treated LPS- and bacteria-induced
sepsis in vivo. They were able to accumulate in the sepsis injured organs and mitigate multiple organ injury.
Compared with free NAD+, NAD+ loaded NPs showed significantly improved therapeutic efficacies.
For this proposed work, we plan to further optimize the NAD+ loaded NPs to achieve even higher drug loading
content and efficiency (Aim 1). The therapeutic mechanism of NAD+-LP-CaP will be studied in vitro in order to
gain a better understanding of how the NAD+ loaded NPs suppress inflammation and also protect cells including
immune cells and endothelial cells from inflammation-induced cell damage (Aim 2). Finally, we will systematically
determine the safety, pharmacokinetics, and therapeutic efficacy of the NAD+ loaded NPs in two representative
mouse sepsis models, and also study the NP’s impact on immune and vascular homeostasis (Aim 3).
If successful, this proposed study will create an innovative, safe, and effective therapeutic approach for treating
sepsis. A translational success of this p...

## Key facts

- **NIH application ID:** 10448923
- **Project number:** 1R21AI165977-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,375
- **Award type:** 1
- **Project period:** 2022-04-22 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448923

## Citation

> US National Institutes of Health, RePORTER application 10448923, Development of NAD+ loaded nanoparticles as a safe and efficient strategy to combat sepsis. (1R21AI165977-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448923. Licensed CC0.

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