We have combined a versatile and powerful route to deliver nucleic acids with peptide-based cell-specific targeting. siRNA targeting the polo-like kinase gene is in clinical trials for cancer treatment, and here we deliver this RNA selectively to cancer cells displaying the neuropilin-1 epitope using gold nanoshells. Release of the siRNA from the nanoparticles results from irradiation with a pulsed near-infrared laser, which also provides efficient endosomal escape within the cell. As a result, our approach requires 10-fold less material than standard nucleic acid transduction materials and is significantly more efficient than other particle-based methods. We also describe a particle–nucleic acid design that does not rely on modified RNA, thereby making the preparation of these materials more efficient and much less expensive. These improvements, when combined with control over when and where the siRNA is released, could provide the basis for diverse cell biological studies.

The laser fluence to trigger nanobubbles around hollow gold nanoshells (HGN) with near infrared light was examined through systematic modification of HGN size, localized surface plasmon resonance (LSPR), HGN concentration, and surface coverage. Improved temperature control during silver template synthesis provided monodisperse, silver templates as small as 9 nm. 10 nm HGN with < 2 nm shell thickness were prepared from these templates with a range of surface plasmon resonances from 600 – 900 nm. The fluence of picosecond near infrared (NIR) pulses to induce transient vapor nanobubbles decreased with HGN size at a fixed LSPR wavelength, unlike solid gold nanoparticles of similar dimensions that require an increased fluence with decreasing size. Nanobubble generation causes the HGN to melt with a blue shift of the LSPR. The nanobubble threshold fluence increases as the irradiation wavelength moves off the nanoshell LSPR. Surface treatment did not influence the threshold fluence. The threshold fluence increased with decreasing HGN concentration, suggesting that light localization through multiple scattering plays a role. The nanobubble threshold to rupture liposomes is 4 times smaller for 10 nm than for 40 nm HGN at a given LSPR, allowing us to use HGN size, LSPR, laser wavelength and fluence to control nanobubble generation.

This work describes a technique for forming nanometer-scale pixilated lipid domains that are self-organized into geometric patterns residing on a square lattice. In this process, a lipid multibilayer stack is deposited onto a silica substrate patterned with a square lattice array of bumps, hemispherical on their sides, formed by electron beam lithography. Domain patterns are shown to be confined to the flat grid between the bumps and comprised of connected and individual domain pixels. Analysis of lattices of varying sizes shows that domain pattern formation is driven by mechanical energy minimization and packing constraints. We demonstrate single lattice sizes and a gradient in lattice size varying from the micrometer to the 100 nm scale applicable to precise arraying, patterning, and transport of biomolecules that partition to lipid domains.

Remote and minimally‐invasive modulation of biological systems with light has transformed modern biology and neuroscience. However, light absorption and scattering significantly prevents penetration to deep brain regions. Herein, we describe the use of gold‐coated mechanoresponsive nanovesicles, which consist of liposomes made from the artificial phospholipid Rad‐PC‐Rad as a tool for the delivery of bioactive molecules into brain tissue. Near‐infrared picosecond laser pulses activated the gold‐coating on the surface of nanovesicles, creating nanomechanical stress and leading to near‐complete vesicle cargo release in sub‐seconds. Compared to natural phospholipid liposomes, the photo‐release was possible at 40 times lower laser energy. This high photosensitivity enables photorelease of molecules down to a depth of 4 mm in mouse brain. This promising tool provides a versatile platform to optically release functional molecules to modulate brain circuits.