Synergistic Lysosomal Impairment and ER Stress Activation for Boosted Autophagy Dysfunction Based on Te Double-Headed...

Area of Science:

• Nanomedicine
• Cancer Therapy
• Autophagy Regulation

Background:

• Autophagy dysfunction is a therapeutic strategy for cancer, but conventional methods targeting only lysosomal impairment have limited efficacy.
• Tumor cells often have compromised autophagy, necessitating novel approaches to enhance therapeutic outcomes.
• Existing autophagy dysfunction strategies are often one-way, limiting their overall effectiveness in tumor treatment.

Purpose of the Study:

• To develop an innovative pharmacological strategy that combines endoplasmic reticulum (ER) stress induction with lysosomal impairment to enhance autophagy dysfunction for tumor therapy.
• To synthesize and characterize tellurium double-headed nanobullets (TeDNBs) modified with human serum albumin (HSA) and omeprazole (OME) for enhanced tumor cell internalization and therapeutic effect.
• To evaluate the in vitro and in vivo therapeutic efficacy of the synthesized TeDNBs-HSA/OME (TeDNBs-HO) nanoagent.

Main Methods:

• Preparation of tellurium double-headed nanobullets (TeDNBs) modified with human serum albumin (HSA) and omeprazole (OME).
• Induction of ER stress via tellurite (TeO3^2-) production in a hydrogen peroxide-rich tumor environment, leading to upregulation of phosphorylated eukaryotic translation initiation factor 2 (P-eIF2α) and autophagy overstimulation.
• Lysosomal impairment by OME, downregulating lysosomal-associated membrane protein 1 (LAMP1) and blocking autolysosome formation.

Main Results:

• The synthesized TeDNBs-HO nanoagent effectively stimulates ER stress, leading to autophagy overstimulation in tumor cells.
• TeDNBs-HO successfully impairs lysosomal function by downregulating LAMP1, thereby blocking autolysosome formation.
• Both in vitro and in vivo studies demonstrated excellent therapeutic efficacy of TeDNBs-HO through the dual mechanism of autophagy dysfunction.

Conclusions:

• The developed TeDNBs-HO nanoagent represents a promising theranostic approach for effective tumor therapy by inducing autophagy dysfunction via ER stress and lysosomal damage.
• This innovative strategy overcomes the limitations of conventional one-way autophagy dysfunction methods, offering enhanced therapeutic potential.
• TeDNBs-HO exhibits potential as a theranostic nanoagent for improved cancer treatment outcomes.