Insight into cyclodextrin hybrid framework formation mechanism to develop a universal vehicle for improving mitochondrial homeostasis

Abstract

Concept of organic anion-γ-cyclodextrin (γ-CD)-containing hybrid framework (CD-HF-1) was proposed for developing novel complex materials. Herein, we revealed the formation mechanisms of a series of organic anion-CD-HF-1 and found organic anion-CD-HF-1 is a promising delivery system. Employing pyrroloquinoline quinone (PQQ) as a representative organic anion, we elaborated the two stages of PQQ-CD-HF-1 formation. Kinetic analysis of PQQ-CD-HF-1 formation revealed that at stage I, PQQ anions encapsulate into CD-MOF-1 and bind to K⁺ cations, partially retaining the crystallinity of CD-MOF-1 and exhibiting excellent water solubility. At stage II, PQQ anions displace γ-CD, leading to γ-CD dissolving in solvent. Meanwhile, PQQ expose on framework surface and gradually co-crystallize with DMF, forming a rod-like structure with significantly reduced water solubility. The crystalline state of PQQ-CD-HF-1 serves as the defining parameter distinguishing these two stages. The spontaneous synthesis of PQQ-CD-HF-1 is driven by electrostatic interactions. PQQ-CD-HF-1 formed at stage I has a desirable PQQ loading capacity achieving surprising 48.7 %. Functionally, PQQ-CD-HF-1 prepared at the first stage significantly enhances stress resistance in Caenorhabditis elegans (C. elegans), particularly under heat and oxidative stress, by maintaining protein homeostasis. Furthermore, PQQ-CD-HF-1 stimulates mitochondrial biogenesis and improves overall mitochondrial function by activating the AMP-activated protein kinase (AMPK) signaling pathway in C. elegans. This study provides new insights into the design and functional applications of hybrid frameworks, highlighting the potential of PQQ-CD-HF-1 in improving stress resistance and regulating mitochondrial homeostasis.