Senescent tumor cell membrane–based “time engine” nanosystem amplifies endoplasmic reticulum targeting for metastasis blockade

As an important component of biomimetic drug delivery systems, cell membrane–coated nanoparticles are widely used for subcellular delivery. However, the influence of cell membranes at different life cycles on subcellular delivery remains unexplored. Our previous study demonstrated that senescent tumor cell membrane–coated nanoparticles (SNP) displayed superior endoplasmic reticulum (ER) targeting efficiency in tumor cells. After inducing tumor cells into senescence, SNP showed greater accumulation in ER. Herein, we design a “time engine” nanosystem for amplified ER targeting: Firstly, ribociclib is encapsulated into SNP (R@SNP) to induce tumor cell senescence; then, SNP loaded with brefeldin A (B@SNP) is used to trigger ER stress. By sequential therapy, R@SNP disrupts the cytoskeleton of 4T1 tumor cells to eliminate ER-targeting barriers and remodels the tumor immune microenvironment; B@SNP boosts ER-targeting efficiency and triggers intense ER stress. Collectively, such time engine nanosystem achieves excellent ER accumulation and antimetastatic efficacy in 4T1 tumor–bearing mice, providing an innovative perspective for subcellular delivery and tumor treatment.