Efficient transplantation of STING protein-enriched endoplasmic reticulum for tumor immunotherapy via ionizable membrane fusion liposome

Abstract

The epigenetic silencing of the cGAS-STING pathway in cancer cells significantly compromises tumor immune surveillance, posing a major challenge in immunotherapy. To address this, we developed an ionizable membrane fusion liposome system capable of transplanting STING protein-enriched endoplasmic reticulum (ER) directly into the cytosol of cancer cells, thereby reactivating the suppressed STING pathway. By modifying the liposomes with demethylcantharidin (DMC, an antitumor drug), the system maintains a neutral surface charge under physiological conditions, which enhances circulation stability and reduces hepatic clearance. In the mildly acidic tumor microenvironment, DMC cleavage induces a charge reversal of liposomes, thereby restoring membrane fusion capability and facilitating tumor-specific accumulation. Reactivation of the STING pathway in tumor cells, combined with DMC-induced tumor antigen release, synergistically stimulates immune cell recruitment, effectively transforming immunologically “cold” tumors into “hot” tumors. This therapeutic strategy leverages endogenous organelle-derived biomaterials to restore cellular functions by directly delivering functional proteins and bioactive components into the cytosol. Altogether, our study provides a mechanistic rationale and therapeutic proof-of-concept for harnessing natural biological materials and their composites to enable innovative treatments for complex diseases.