A research team at Yangzhou University’s Institute of Translational Medicine introduces a LepR-targeted nitric oxide nanopump (CB-LepR) that chemically excites BNN6 using endogenous H₂O₂ to achieve sustained in situ NO release within senescent LepR⁺ cells. This approach scavenges excess H₂O₂, reactivates glycolysis signaling, and restores HSC niches, vascular and neural support, effectively reversing age-induced bone marrow collapse in murine models.
Key points
CB-LepR nanopump co-encapsulates CPPO and BNN6 in a DSPE-PEG-MAL/soybean oil matrix functionalized with a LepR antibody for targeted delivery.
Elevated H₂O₂ in aged bone marrow initiates peroxyoxalate chemiexcitation to produce ¹,²-dioxetanedione, directly exciting BNN6 and triggering sustained intracellular NO release.
Targeted NO release in LepR⁺ cells reactivates glycolysis, reduces senescence markers, and restores hematopoietic, vascular, lymphatic, and neural support in aged murine bone marrow.
Why it matters:
This targeted nanodelivery system offers a paradigm-shifting strategy to restore aging bone marrow function and combat age-related hematopoietic decline.
Q&A
What are LepR⁺ cells?
How does the peroxyoxalate-based chemiexcitation mechanism work?
Why target H₂O₂ in aged bone marrow?
How does nitric oxide restore glycolysis in senescent cells?
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Academy
Nitric Oxide in Aging and Regeneration
Overview: Nitric oxide (NO) is a simple, gaseous molecule that plays diverse roles in cellular signaling. In the context of aging and regenerative medicine, NO can modulate metabolic pathways, blood vessel function, immune responses, and cell survival. Recent nanotechnology approaches harness NO release to rejuvenate aged tissues, including bone marrow.
What Is Nitric Oxide?
Nitric oxide is a diatomic free radical produced by nitric oxide synthase (NOS) enzymes in many cell types. It diffuses rapidly across cell membranes and acts on nearby cells to regulate processes such as blood vessel dilation, neurotransmission, and immune defense. In low physiological concentrations, NO promotes cell signaling and homeostasis; in excess, it can contribute to oxidative stress.
NO Biosynthesis Pathways
- Endogenous NOS Enzymes: Three main isoforms—eNOS (endothelial), nNOS (neuronal), and iNOS (inducible)—convert L-arginine to NO and L-citrulline.
- Nitrate-Nitrite Pathway: Dietary nitrates can be reduced by oral bacteria and tissues to nitrite and then to NO under low-oxygen conditions.
Role of NO in Aging
During aging, NO production often declines due to reduced NOS activity and cofactor availability. Lower NO levels contribute to impaired blood flow, diminished immune surveillance, and aberrant cellular metabolism. Conversely, oxidative stress can lead to excessive reactive nitrogen species that damage proteins and DNA, accelerating tissue dysfunction.
NO and Cellular Metabolism
NO regulates metabolic pathways by modulating key enzymes:
- Glycolysis: NO enhances glucose uptake by upregulating glucose transporters and activating glycolytic enzymes, supporting ATP production in stressed or senescent cells.
- Mitochondrial Function: At low doses, NO can reversibly inhibit mitochondrial respiration to shift metabolism toward glycolysis, a process known as the Warburg effect in repair contexts.
Nanopump Technology for NO Delivery
Traditional NO delivery methods face challenges such as short half-life and poor tissue targeting. Nanopump systems co-encapsulate NO donors (e.g., BNN6) and chemiluminescent substrates (e.g., CPPO) within biocompatible polymers. Elevated hydrogen peroxide in aged tissues triggers peroxyoxalate chemiexcitation, generating an energized intermediate that directly excites the NO donor, releasing NO where it is needed.
Applications in Bone Marrow Regeneration
Bone marrow aging leads to reduced hematopoietic stem cell (HSC) support, vascular decline, and immune dysfunction. Targeted NO nanopumps deliver controlled NO release within leptin receptor–expressing stromal cells (LepR⁺), rejuvenating their metabolism, restoring glycolysis, reducing senescence markers, and rebuilding the HSC niche.
Advantages for Longevity Science
- Precision: Chemiexcitation uses age-associated markers (H₂O₂) for spatial control.
- Sustainability: Polymer and oil components prolong NO half-life.
- Minimal Invasiveness: Local or systemic delivery allows non-invasive treatment.
By integrating nanotechnology with an understanding of NO biology, researchers are pioneering new longevity interventions that restore tissue function and extend health span.
