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Mining a large cohort of single-cell transcriptomics data, here we employ combinatorial optimization techniques to chart the landscape of optimal combination therapies in cancer. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient for killing at least 80% of tumor cells while sparing at least 90% of nontumor cells in the tumor microenvironment. However, as more stringent and selective killing is required, the number of targets needed rises rapidly. Emerging individual targets include PTPRZ1 for brain and head and neck cancers and EGFR in multiple tumor types. In sum, this study provides a computational estimate of the identity and number of targets needed in combination to target cancers selectively and precisely., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.

Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance.