Cell membrane-coated mesoporous silica nanorods overcome sequential drug delivery barriers against colorectal cancer

Local delivery of nanomedicines holds therapeutic promise for colorectal cancer (CRC). However, it presents tremendous challenges due to the existence of multiple physiological barriers, especially intracellular obstacles, including intracellular trafficking, subcellular accumulation, and drug release. Herein, we report a multifunctional nanoparticle (CMSNR) by wrapping the mesoporous silica nanorod with cell membrane derived from CRC cells for improved chemotherapy. Compared with their naked counterparts, the cell membrane endowed CMSNR with homotypic targeting and improved cellular uptake capacities. Due to the rod-like shape, CMSNR achieved superior colorectal mucus permeability, enhanced tumor accumulation, and boosted cellular uptake than their spherical counterparts. Moreover, the internalized CMSNR underwent robust intracellular trafficking and gained augmented motility toward the nucleus, leading to efficient perinuclear accumulation and a subsequent 5.6-fold higher nuclear accumulation of loaded drug than that of nanospheres. In the orthotopic colorectal tumor-bearing nude mice, rectally administrated mefuparib hydrochloride (MPH)-loaded CMSNR traversed the colorectal mucus, penetrated the tumor tissue, and successfully aggregated in the perinuclear region of cancer cells, thus exhibiting significantly improved antitumor outcomes. Our findings highlight the shape-based design of cell membrane-coated nanoparticles that can address sequential drug delivery barriers has a promising future in cancer nanomedicine.