An ER–Horse Detonating Stress Cascade for Hepatocellular Carcinoma Nanotherapy

Persisting and excessive endoplasmic reticulum stress (ERS) can evoke rapid cell apoptosis. Therapeutic interference of ERS signaling holds enormous potentials for cancer nanotherapy. Herein, a hepatocellular carcinoma (HCC) cell–derived ER vesicle (ERV) encapsulating siGRP94, denoted as ER–horse, has been developed for precise HCC nanotherapy. Briefly, ER–horse, like Trojan horse, was recognized via homotypic camouflage, imitated physiological function of ER and exogenously opened the Ca²⁺ channel. Consequently, the mandatory pouring–in of extracellular Ca²⁺ triggered the aggravated stress cascade (ERS and oxidative stress) and apoptosis pathway with the inhibition of unfolded protein response by siGRP94. Collectively, our findings provide a paradigm for potent HCC nanotherapy via ERS signaling interference and exploring therapeutic interference of physiological signal transduction pathways for precision cancer therapy.