Combinatorial screening of nanomedicines in patient-derived cancer organoids facilitates efficient cancer therapy

Patient-derived tumor organoids (Pat.-ORG) have emerged as invaluable tools for identifying synergistic drug combinations, including the precise types and proportions of combined drugs, to guide efficacious therapy. However, the variability in pharmacokinetic profiles among different medications can significantly impact the tumor accumulation of the in vitro screened drug regimens, potentially compromising their ultimate in vivo therapeutic efficacy. Given the remarkable capacity of nanocarriers to deliver multiple drugs with diverse physicochemical properties and to harmonize their in vivo metabolic characteristics, we propose leveraging Pat.-ORG-based drug combination screening using nanomedicine to bridge the gap between in vitro and in vivo outcomes that traditional drug screening methods often encounter. In this study, 15 exquisitely engineered nanomedicines were combined at five distinct drug ratios, yielding 525 unique nanomedicine combinations that were rigorously screened using colorectal cancer organoids to identify those exhibiting remarkable synergistic effects. In vivo experiments validated that the selected nanomedicine combinations demonstrated superior antitumor efficacy compared to their free-drug counterparts. Our research underscores the immense potential of integrating organoid modeling with nanomedicine technology to optimize combination treatment screening and advance the development of effective cancer therapies.