Significance: Cells have been shown to respond to a host of physical properties of the environments that surround them. However, given that these properties vary considerably across tissues, how these individual properties interact to form unique regulatory environments for cells is largely unknown. This work analyzes the transcriptional responses of cells to unique combinations of microenvironmental material properties to gain broad insights into the coupling among different properties, the magnitude of the transcriptional effects, and the role of cell type. We find significant coupling among these properties, large variation in the magnitude of the transcriptional changes, and qualitative differences in the responses based on cell type, demonstrating the significant context dependence of microenvironmental material sensing.

The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on theSalmonella typhimuriumbacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB.