AMFR-mediated ER-phagy regulation and therapeutic targeting in osteosarcoma: a multifunctional nanoplatform strategy

  • J Nanobiotechnology. 2025 Nov 18;23(1):717. doi: 10.1186/s12951-025-03754-8.
Qirui Zhao  #  1  2 ,  Xiaoqing Lu  #  1  2 ,  Tongtong Xu  3 ,  Zixuan Gao  2 ,  Linjia Peng  2 ,  Binyu Zhu  4 ,  Weicheng Wang  4 ,  Zhigang Liu  1 ,  Guangjie Yang  1 ,  Hui Zhao  5 ,  Zhiming Song  6 ,  Qiankun Lou  1  2 ,  Jiaming Li  1  2 ,  Zhiguang Ren  2 ,  Zhe Yu  2 ,  de la Fuente Jesus M  4  7 ,  Daxiang Cui  8  9
Affiliations
  • 1. Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, 475000, China.
  • 2. Medical and Engineering Cross Research Institute, The First Affiliated Hospital of Henan University, No. 357 Ximen Street, Kaifeng, 475000, Henan Province, China.
  • 3. GCP lab, The First Affiliated Hospital of Henan University, Kaifeng, 475000, China.
  • 4. Institute of Nano Biomedicine and Engineering, School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai JiaoTong University, No. 800 Dongchuan Road, Shanghai, 200240, China.
  • 5. Department of Vascular Surgery, The First Affiliated Hospital of Henan University, Kaifeng, 475000, China.
  • 6. Department of Cardiology, The First Affiliated Hospital of Henan University, Kaifeng, 475000, China.
  • 7. Instituto de Nanociencia y Materiales de Aragon, CSIC-University of Zaragoza and CIBER-BBN, Zaragoza, 50009, Spain.
  • 8. Medical and Engineering Cross Research Institute, The First Affiliated Hospital of Henan University, No. 357 Ximen Street, Kaifeng, 475000, Henan Province, China. [email protected].
  • 9. Institute of Nano Biomedicine and Engineering, School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai JiaoTong University, No. 800 Dongchuan Road, Shanghai, 200240, China. [email protected].
  • # Contributed equally.
PMID: 41250206 DOI: 10.1186/s12951-025-03754-8
Abstract

This work explores how Autocrine Motility Factor Receptor (AMFR)-driven ubiquitination of Family with Sequence Similarity 134 Member B (FAM134B) in hypoxia adaptation and endoplasmic reticulum-selective Autophagy (ER-phagy) in osteosarcoma (OS), aiming to develop a stimuli-responsive nanoplatform (S-SNACs@TPZ@Cas-A) for targeted therapy. Transcriptomic analysis identifies the AMFR-FAM134B axis as crucial for OS survival under hypoxic conditions. The nanoplatform, thoroughly characterized via established methods, co-delivers CRISPR-Cas9 RNP and tirapazamine to disrupt AMFR and enhance Reactive Oxygen Species production, inhibiting tumor growth in mouse models. In vitro assays confirm decreased FAM134B ubiquitination and ER-phagy inhibition. In vivo, S-SNACs@TPZ@Cas-A reduces tumor volume, metastasis, and enhances immune response without significant toxicity. Second near-infrared window imaging validates targeted drug delivery. This approach provides a precise strategy to disrupt hypoxia tolerance in OS and potentially Other hypoxia-tolerant tumors, offering promise for improved therapeutic outcomes.

Keywords
AMFR-FAM134B axis; CRISPR-Cas9 nanoplatform; Endoplasmic reticulum autophagy; Hypoxia adaptation; Osteosarcoma; Theranostic.
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