Nanoneedles display potential in mediating the delivery of drugs and biologicals, as well as intracellular sensing and single cell stimulation through direct access to the cell cytoplasm. Nanoneedles enable cytosolic delivery, negotiating the cell membrane and the endolysosomal system, thus overcoming these major obstacles to the efficacy of nanotherapeutics. The low toxicity and minimal invasiveness of nanoneedles has a potential for the sustained non-immunogenic delivery of payloads in vivo, provided that the development of biocompatible nanoneedles with a simple deployment strategy is achieved. Here we present a mesoporous silicon nanoneedle array that achieves a tight interface with the cell, rapidly negotiating local biological barriers to grant temporary access to the cytosol with minimal impact on cell viability. The tightness of this interfacing enables both delivery of cell-impermeant quantum dots in vivo and live intracellular sensing of pH. Dissecting the biointerface over time elucidated the dynamics of cell association and nanoneedle biodegradation, showing rapid interfacing leading to cytosolic payload delivery within less than 30 minutes in vitro. The rapid and simple application of nanoneedles in vivo to the surface of tissues with different architectures invariably resulted in the localized delivery of quantum dots to the superficial cells and their prolonged retention. This investigation provides an understanding of the dynamics of nanoneedles’ biointerface and delivery outlining a strategy for highly local intracellular delivery of nanoparticles and cell-impermeant payloads within live tissues.

Porous silicon nanoneedles can map Cathepsin B activity across normal and tumor human esophageal mucosa. Assembling a peptide‐based Cathepsin B cleavable sensor over a large array of nano­needles allows the discrimination of cancer cells from healthy ones in mixed culture. The same sensor applied to tissue can map Cathepsin B activity with high resolution across the tumor margin area of esophageal adenocarcinoma.

Page 5504. The amended caption for Figure 3 should read as follows: Figure 3. CellÀnanoneedle interface upon nanoinjection. (aÀc) nN-T nanoinjection showing cytosolic interfacing and exclusion from the nucleus 1 min following nanoinjection. (dÀf) Temporal evolution of nN-B nanoinjection showing progressive cytosolic interfacing and nuclear exclusion with associated remodeling of the nuclear envelope. (a,d) Laser scanning confocal micrographs at the time points indicated. The cell presented in nN-B 4 h is also presented in our previous study with different YZ and XZ projections. 6 Cell membrane is in red, nuclei are in blue, and nanoneedles are in green. (b,e) FIB-SEM cross sections of nanoinjected cells. (c,f) 54°tilt SEM micrographs showing retained cell morphology. (g) Three-dimensional reconstruction FIB-SEM slice through segmentation at different times for nN-B nanoinjection. Nanoneedles are in blue, cell membrane is in purple, nuclear envelope is in yellow, and electron dense areas attributed to Si are in green (72 h). (h) Quantification of the nanoneedle depth of cytosolic interfacing, measured as the distance between the tip of the nanoneedle and the underlying cell membrane. (i) Quantification of the distance of nanoneedles from the nucleus, measured as the distance between the tip of a nanoneedle and the cell nucleus.

Conjugated polymers possess excellent qualities as fluorescent probes for biomedical applications, because of their extremely high brightness, extinction coefficients, and photostability. Encapsulating these hydrophobic polymers in nanoparticulate form allows transfer to aqueous environments and construction of high-performance fluorescent nanoparticle constructs, and several surface capping strategies have been demonstrated to date. Here, we describe the development of a new class of multifunctional capping ligands for conjugated polymer nanoparticles based on custom-designed amphiphilic peptides. These versatile peptide ligands provide a protective hydrophilic capping layer, chemical handles for further conjugation,

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