# K+-H+ coupling strategy for immune regulation and bone defect repair

## TL;DR

This study introduces a new strategy using potassium ions to regulate immune responses and promote tissue repair after severe injuries.

## Contribution

A novel K+-H+ coupling strategy is proposed to modulate macrophage metabolism and tissue regeneration through extracellular K+ elevation.

## Key findings

- Elevated extracellular K+ induces intracellular pH changes, activating the AMPK/Nrf2 axis in macrophages.
- KHCO3@PLV enables precise delivery and ultrasound-triggered K+ release at injury sites.
- The K+-H+ coupling strategy effectively resolves chronic inflammation and promotes tissue repair.

## Abstract

Ion homeostasis is crucial for maintaining cell function. Potassium ion (K+) is one of the most important cations in the human body, and it plays key role in maintaining biological activities and cellular functions, including the intricate balance of ion homeostasis that underpins both physiological and pathological processes. This study explored a novel role of K+ ions in regulating immune cell function and promoting tissue repair, especially in macrophage-mediated environments after severe tissue injury. We designed and synthesized a platelet-liposome vesicles loaded KHCO3 (KHCO3@PLV) that precisely delivered potassium bicarbonate to the site of injury extracellular after intravenous injection; then, precise ultrasound-triggered K+ release regulated extracellular K+ concentrations in the local macrophage environment. These effects collectively validate the K+-H+ coupling strategy - a novel mechanism whereby extracellular K+ elevation induces intracellular pH modulation, subsequently activating the AMPK/Nrf2 axis to reprogram macrophage metabolism and facilitating tissue regeneration through resolution of chronic inflammation. The main conclusion of the study is that an elevated extracellular K+ environment, which is an innovative treatment, is a potentially effective strategy for regulating immune responses and promoting repair after severe tissue injury.

Image 1

•The spatiotemporal correlation between K+ concentration and inflammatory response in the tissue injury microenvironment.•The development of an ion-targeted strategy involving the in situ release of K+ ions.•Design of a K+-H+ coupling immunomodulatory therapy.

The spatiotemporal correlation between K+ concentration and inflammatory response in the tissue injury microenvironment.

The development of an ion-targeted strategy involving the in situ release of K+ ions.

Design of a K+-H+ coupling immunomodulatory therapy.