The practical application of nanoparticles (NPs) as chemotherapeutic drug delivery systems is often hampered by issues such as poor circulation stability and targeting inefficiency. Here, we have utilized a simple approach to prepare biocompatible and biodegradable pHresponsive hybrid NPs that overcome these issues. The NPs consist of a drug-loaded polylactic-co-glycolic acid (PLGA) core covalently 'wrapped' with a crosslinked bovine serum albumin (BSA) shell designed to minimize interactions with serum proteins and macrophages that inhibit target recognition. The shell is functionalized with the acidity-triggered rational membrane (ATRAM) peptide to facilitate internalization specifically into cancer cells within the acidic tumor microenvironment. Following uptake, the unique intracellular conditions of cancer cells degrade the NPs, thereby releasing the chemotherapeutic cargo. The drugloaded NPs showed potent anticancer activity in vitro and in vivo while exhibiting no toxicity to healthy tissue. Our results demonstrate that the ATRAM-BSA-PLGA NPs are a promising targeted cancer drug delivery platform.

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Molecular processes leading to salt stress acclimation in the model cyanobacterium Prochlorococcus are not known. To address this, we used RNA sequencing (RNAseq) to compare the global transcriptome of two exponential-phase populations of Prochlorococcus AS9601 cells - acclimated to high salt (5%, w/v) and normal seawater salt (3.8%, w/v). Experiments showed that salt acclimated cells exhibit slower growth rates with a doubling time almost twice as controls. Approximately 1/3 of the genome was found to be differentially expressed (p-value <0.05), but a considerably large number of these genes are "hypothetical proteins" with unknown function. Transcript abundance were higher for genes involved in respiratory electron flow, carbon fixation, osmolyte/compatible solute biosynthesis and inorganic ion transport. Many of the highly expressed genes are 'high light inducible proteins' believed to be part of the general Prochlorococcus stress response. Transcript abundance were lower for genes involved in photosynthetic electron transport and cell division. The relative reduction in transcript abundance for genes encoding proteins containing heme groups and iron transporters suggests cellular iron requirements in salt acclimated cells maybe lower. The results presented here provide the first glimpse into global gene expression changes in Prochlorococcus cells due to salt stress.

Cancer cells are often characterized by elevated levels of mitochondrion-bound hexokinase II (HKII), which facilitates their survival, proliferation, and metastasis. Here, we have designed a cancer-selective cell-penetrating peptide (CPP) by covalently coupling a short penetration-accelerating sequence (PAS) to the mitochondrial membrane-binding N-terminal 15 amino acids of HKII (pHK). PAS-pHK mediates efficient cellular uptake and cytosolic delivery of a synthetic mimic of miR-126, a tumor suppressor miRNA downregulated in many malignancies. Following uptake by breast cancer MCF-7 cells, the CPP−miRNA conjugate is distributed throughout the cytosol and shows strong colocalization with mitochondria, where PAS-pHK induces depolarization of mitochondrial membrane potential, inhibition of metabolic activities, depletion of intracellular ATP levels, release of cytochrome c, and, finally, apoptosis. Concomitantly, the miR-126 cargo synergistically enhances the anticancer effects of PAS-pHK. Importantly, the PAS-pHK−miR-126 conjugate is not toxic to noncancerous MCF-10A and HEK-93 cells. Our results demonstrate the potential of PAS-pHKmediated delivery of miRNA mimics as a novel cancer-selective therapeutic strategy.