Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.

Abstract

Inspired by the non-transmembrane transfer of mitochondria in cell-to-cell communications, herein, we report an original exploration to accelerate mitochondrial intercellular transport, and its application to exogenous cargo delivery. We discover that deliberate PINK1-targeted mitophagy downregulation elevates mitochondrial transit capacity via multifaceted drivers-morphological adaptation, metabolic reprogramming, and respiratory enhancement. Capitalizing on this, we engineer high-speed mitochondrial vehicles for photosensitizer hitchhiking, with spatiotemporal tracking elucidating its dynamic intercellular transit and physiological impacts. Through mitochondria's communication network-tunneling nanotubes (TNTs), the mitochondria-photosensitizer cotransporter achieves reinforced intercellular delivery, thereby inducing deep tumor penetration and enhanced photodynamic killing. Our work establishes a transformative mitochondria-hitchhiking platform for overcoming biological barriers in drug delivery and provides mechanistic insights into manipulating intercellular organelle transport for therapeutic applications.