Bioinspired 0D mitochondrial bioenergetic actuators rewire cartilage progenitor cell metabolism for osteoarthritis remission.

Abstract

Mitochondrial dysfunction and consequent bioenergetic collapse in cartilage progenitor cells (CPCs), driven by excessive mitochondrial reactive oxygen species (ROS), constitute a fundamental barrier to endogenous cartilage regeneration and accelerate osteoarthritis (OA) progression. Accordingly, precise modulation of mitochondrial ROS is required to restore mitochondrial metabolic homeostasis. However, conventional antioxidant agents such as N-acetylcysteine (NAC) lack cell specificity and organelle-level precision, and exhibit limited bioavailability, thereby restricting their capacity to effectively reestablish mitochondrial metabolic homeostasis. Here, we engineer zero-dimensional (0D) bioinspired nanoassemblies, CPC membrane-coated (3-carboxypropyl)triphenylphosphonium bromide-functionalized NAC-derived carbon quantum dots (CM@TQDs), with capabilities for homotypic recognition and mitochondria-targeted metabolic reprogramming. Subsequently, CM@TQDs are encapsulated within ROS/pH-responsive hydrogel microspheres (HGCT), permitting inflammation-triggered release within the OA joint. Upon HGCT-mediated delivery and cellular internalization, the 0D nanoassemblies accumulate in mitochondria in a membrane potential-dependent manner, enhancing local mitochondrial bioavailability. Mechanistically, HGCT effectively scavenges mitochondrial ROS, restores oxidative phosphorylation, reestablishes tricarboxylic acid cycle flux, and suppresses aberrant glycolytic dependence. This metabolic restoration reactivates PI3K/AKT signaling, mitigates apoptosis and ferroptosis, and promotes CPC proliferation and chondrogenic differentiation. <i>In vivo</i>, HGCT attenuates synovial inflammation and enhances cartilage regeneration, markedly inhibiting OA progression. Collectively, this work establishes a nanobiomimetic therapeutic platform capable of achieving hierarchical precision from cell-specific targeting to organelle-level metabolic regulation, offering a promising strategy for nanoscale bioenergetic intervention in degenerative diseases.