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

  • Nat Commun. 2025 Dec 23. doi: 10.1038/s41467-025-67837-8.
Yiwei Peng  #  1 ,  Datong Gao  #  1 ,  Yiliang Yang  1 ,  Yitian Du  1 ,  Zhenzhen Yang  1 ,  Jiajia Li  1 ,  Meng Lin  1 ,  Yanxia Zhou  1 ,  Xinru Li  1 ,  Xianrong Qi  2
Affiliations
  • 1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
  • 2. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, PR China. [email protected].
  • # Contributed equally.
PMID: 41436474 DOI: 10.1038/s41467-025-67837-8
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.

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