Synergistic Lysosomal Impairment and ER Stress Activation for Boosted Autophagy Dysfunction Based on Te Double‐Headed Nano‐Bullets

Abstract To overcome the autophagy compromised mechanism of protective cellular processes by “eating”/“digesting” damaged organelles or potentially toxic materials with autolysosomes in tumor cells, lysosomal impairment can be utilized as a traditional autophagy dysfunction route for tumor therapy; however, this conventional one‐way autophagy dysfunction approach is always limited by the therapeutic efficacy. Herein, an innovative pharmacological strategy that can excessively provoke autophagy via endoplasmic reticulum (ER) stress is implemented along with lysosomal impairment to enhance autophagy dysfunction. In this work, the prepared tellurium double‐headed nanobullets (TeDNBs) with controllable morphology are modified with human serum albumin (HSA) which facilitates internalization by tumor cells. On the one hand, ER stress can be stimulated by upregulating the phosphorylation eukaryotic translation initiation factor 2 (P‐eIF2α) owing to the production of tellurite (TeO 3 2− ) in the specifical hydrogen peroxide‐rich tumor environment; thus, autophagy overstimulation occurs. On the other hand, OME can deacidify and impair lysosomes by downregulating lysosomal‐associated membrane protein 1 (LAMP1), therefore blocking autolysosome formation. Both in vitro and in vivo results demonstrate that the synthesized TeDNBs‐HSA/OME (TeDNBs‐HO) exhibit excellent therapeutic efficacy by autophagy dysfunction through ER stress induction and lysosomal damnification. Thus, TeDNBs‐HO is verified to be a promising theranostic nanoagent for effective tumor therapy.