Dual Targeting of m 7 G tRNA Modification and Histone Acetylation using Carrier‐Free Nano‐Epidrugs to Evoke Osteosarcoma Chemosensitization

Abstract Osteosarcoma has witnessed stagnant clinical outcomes over the past four decades, owing to the inevitable reduction in chemosensitivity during treatment. Although epigenetics offers promising strategies to augment chemosensitivity, its role in osteosarcoma remains elusive. Here, by analyzing clinical cohorts, it is found that the aberrant overexpression of methyltransferase 1 (METTL1), a key N 7 ‐methylguanosine (m 7 G) modulator, and histone deacetylase 1 (HDAC1), associated with poor chemotherapeutic response in osteosarcoma. To target these epigenetic vulnerabilities, innovative carrier‐free nano‐epidrugs (siMBD‐R NPs) are developed, incorporating first‐line doxorubicin (DOX) with siRNA against METTL1 (siMETTL1), FDA‐approved HDAC inhibitor belinostat (BEL), and DSPE‐PEG 2000 ‐cRGD. With ultrahigh active pharmaceutical ingredient (API) loading content (≈92.7 wt.%), tumor‐specific targeting capability, and unique pH‐responsive release characteristics, the siMBD‐R NPs indicate remarkable tumor accumulation (15.2‐fold enhancement) compared to free siMETTL1. Importantly, through dual‐epigenetic regulation, the nano‐epidrugs markedly amplify DOX‐triggered DNA damage. Specifically, siMETTL1 selectively disrupts m 7 G‐modified tRNA‐mediated translation of DNA repair proteins, and BEL‐induced HDAC inhibition remodels chromatin into a more accessible state, promoting DNA damage accumulation. In vivo studies demonstrate that siMBD‐R NPs can significantly potentiate chemosensitivity, achieving an 81.5% relative increase in tumor inhibition, and can activate an immune response. This work highlights the potential benefits of leveraging dual‐targeted epigenetic intervention to evoke osteosarcoma chemosensitization.