Exploiting the Warburg Effect: Co‐Delivery of Metformin and FOXK2 siRNA for Ovarian Cancer Therapy

Abstract

Ovarian cancer remains a significant health issue worldwide, often facing limitations in treatment due to side effects and drug resistance. Tumor cells typically undergo the “Warburg effect,” preferring glycolysis, which leads to their rapid growth and survival. Metformin, a widely used diabetes medication, targets 5' adenosine monophosphate‐activated protein kinase (AMPK), reducing glycolysis and thereby slowing tumor growth. Additionally, forkhead box protein K2 (FOXK2), a transcription factor often found in excess in many tumors, promotes glycolysis and tumor development. Delivering metformin and FOXK2 siRNA directly to the tumor site in the body is challenging due to the metformin's poor water solubility and the fragile nature of siRNA. To address this, zirconium and 5,10,15,20‐tetra(4‐pyridyl)porphyrin nanoparticles loaded with FOXK2 siRNA, enveloped in cell membrane, co‐encapsulated with metformin in gelatin methacrylate microspheres (ZrTCP@siFOXK2@CM/Met@GelMA) hydrogel microspheres are developed for effective dual delivery. These microspheres facilitate targeted drug delivery, photothermal therapy with near‐infrared light, and interference with glucose metabolism. These results show that infrared light combined with metformin and FOXK2 siRNA successfully activates the AMPK pathway, reducing ovarian cancer growth. This method offers a promising new direction in treatment, utilizing the complex metabolic characteristics of ovarian cancer to achieve better results.