A Self‐Framed Nanoprodrug for Orchestrating Mitochondria‐Associated Membranes‐Mediated Cascade Amplification Loop to Potentiate Radiotherapy in Esophageal Squamous Cell Carcinoma

ABSTRACT Radioresistance remains a pivotal factor in the failure of esophageal squamous cell carcinoma (ESCC) therapy. Here we report a hyaluronic acid‐modified, polyphosphazene‐based self‐scaffold nanoradiosensitizer (HDiSeH) that addresses the limitations of single‐organelle targeting. HDiSeH exhibited uniform nanoscale morphology, ultrahigh dihydromyricetin (Di) loading (77.8%), and tumor microenvironment‐relevant pH/reactive oxygen species (ROS)/X‐ray responsive release. In ESCC cells, HDiSeH markedly enhanced radiosensitivity, increasing γ‐H2AX foci, suppressing DNA damage repair, and abolishing clonogenic survival. Mechanistically, HDiSeH remodeled mitochondria‐associated membranes (MAMs), inducing robust endoplasmic reticulum stress (CHOP up 4.8‐fold) and a cytosolic Ca 2+ surge (10.2‐fold), which drived mitochondrial Ca 2+ overload (4.8‐fold), a burst of mitochondrial ROS (9.7‐fold), loss of mitochondrial membrane potential, and bioenergetic collapse (ATP to 40.3% of control), culminating in mitochondria‐dependent apoptosis. In a KYSE‐150 xenograft mouse model, HDiSeH demonstrated good biological safety and sensitized tumors to radiotherapy. Specifically, radiotherapy combined with high‐dose HDiSeH achieved potent tumor growth inhibition (89.0%) and significantly extended median survival with favorable tolerability. Overall, our study advances a radiosensitization paradigm that targets inter‐organelle communication to build an endogenous signal amplification network, offering an efficient and safe strategy to overcome ESCC radioresistance.