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

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.