A Remote-Controlled Nanopump Delivers Oxygen to Boost Energy Production in Osteoarthritis.

Abstract

The pro-energy synthesis strategy has been considered a promising approach for addressing degenerative disorders, including osteoarthritis (OA). However, the physiologically low oxygen tension in articular cartilage limits aerobic respiration and energy production. In this study, a hemoglobin (Hb)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanopump was developed for efficient oxygen delivery. This nanopump was further functionalized with cartilage-targeting peptides (CZIF@Hb) and specifically guided to aggregate on chondrocytes. In response to active (ultrasonic driving) and passive stimuli (acidic microenvironment), CZIF@Hb underwent responsive disassembly. ZIF-8 drove CO₂ adsorption, while Hb facilitated O₂ release. These processes synergistically enhanced the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation (OXPHOS), thereby promoting adenosine triphosphate (ATP) generation. Mechanistically, in addition to direct oxygen supply, CZIF@Hb nanopump indirectly facilitated the incorporation of α-KG into the TCA cycle by activating the solute carrier family 1 member 5 (SLC1A5)/solute carrier family 38 member 2 (SLC38A2)-glutamate dehydrogenase 1 (GLUD1)-glutaminase (GLS) axis. The enhanced energy metabolism mitigated free radical-induced damage and concurrently promoted the formation of hyaline cartilage instead of fibrocartilage. Administration of CZIF@Hb nanopump exerted therapeutic effects on cartilage degeneration, subchondral bone sclerosis, and synovial inflammation. Overall, the oxygen-carrying nanoplatform offers a feasible strategy for overcoming energy deficits in hypometabolic organs.