MMP-Responsive PEGylated Graphene Oxide Nanocarriers for miRNA Delivery in Colorectal Cancer

Abstract

Colorectal cancer is one of the major causes of morbidity and mortality in cancer patients globally, and there is an immediate need to develop more specific and effective treatment methods. mRNAbased therapeutics have become promising molecular interventions because they can regulate multiple oncogenic pathways, but poor stability, rapid degradation, off-target effects, and inefficient tumor delivery are limitations to their clinical translation. PEGylated, matrix metalloproteinase-responsive graphene oxide nanocarriers are the new generation of enzymedirected delivery platforms capable of bypassing those barriers. Graphene oxide provides a high loading capacity and protection for miRNA, and PEGylation increases systemic stability, biocompatibility, and extended circulation via stealth effects. PEG shedding and focal release of miRNA are triggered by the incorporation of matrix metalloproteinase-cleavable peptide linkers, resulting in tumor-selective activation due to the high matrix metalloproteinase-2/9 levels in the colorectal tumor microenvironment. After cellular uptake and endosomal escape, transferred miRNAs bind the RNA-induced silencing complex to execute sequence-specific gene silencing, thereby inducing apoptosis, suppressing proliferation and metastasis, and sensitizing to chemotherapy. This review highlights the present-day design strategies, biological processes, preclinical success, co-delivery methods, and translational issues of matrix metalloproteinasesensitive GO-PEG miRNA systems. Together, these intelligent nanocarriers provide a potential nanomedicine platform for targeted therapy in CRC.