The gastrointestinal tract is an eight-meter-long pathway that includes various organs,which runs from the mouth to the anus.Under certain pathological circumstances,tumors can develop in one of these organs.Although these tumors could be surgically removed at an early stage of their development,the disease could be incurable and fatal if they progress.In this article,we review our recent progress in the development of a series of rationally designed mesoporous silica nanoparticles (MSNP),which includes the use of a supported lipid bilayer (a.k.a.silicasome),to provide more efficacious and well-tolerated chemotherapy and/or chemo-immunotherapy for the different types of gastrointestinal (GIT) cancer,such as pancreatic ductal adenocarcinoma(PDAC) and colorectal cancer (CRC).Through the use of our silicasome platform,we were able to deliver single-drug or synergistic drug combinations to orthotopic PDAC tumors in murine Kras and human-derived PDAC models.We also developed a scalable silicasome formulation for the weak-base anticancer drug,irinotecan,leading to a highly potent treatment option for mice with reduced toxicity.To address the complex and heterogeneous tumor microenvironment (TME),we have discussed the impact of stroma nanoengineering by transcytosis activation or vascular access improvement,which could enhance the effec-tiveness ofnanocarriers in vivo.Recently,we have upgraded our drug-delivering silicasome as a chemoimmunotherapy platform that implements immunogenic cell death (ICD) as an endogenous vaccination approach.When cointerference occurs in re-gionally overexpressed immune checkpoint pathways,it was possible to generate a “hot” tumor microenvironment and pro-pagate anticancer immunity,leading to long-lasting anticancer effects.These advanced preclinical results are promising and expected to generate a positive impact by providing efficacious and safe nanocarriers that can be placed into the pipeline of novel nanomedicine for the management of GIT cancer.