Nanoneedles display great potential as a facile, high-throughput, minimally invasive strategy for intracellular investigation due to their low-cost, versatility and ease of use^[1]. Nanoneedles can interface efficiently with cells, with minimal effects on their survival and proliferation. Both sensing of the intracellular milieu and delivery to the cell cytosol can be achieved by nanoneedles with higher accuracy and lower invasiveness that currently established methods. Metal assisted chemical etch (MACE) is emerging as a low-cost, high-throughput, versatile strategy for the synthesis of high aspect ratio silicon nanostructures, including nanowires and nanoneedles^[2]. MACE allows fine control over the geometry and porous structure of nanoneedles by tuning a limited number of etch parameters. Here we will review the latest advancements in the development of porous silicon nanoneedles by metal assisted chemical etch and their applications for intracellular delivery. An initial systematic exploration of the MACE phase space indicates that controlling substrate resistivity, concentration of H2O2 and HF and catalytic metal determines the formation of solid and porous nanowires as well as electropolished surfaces^[3]. By developing a process combining MACE with semiconductor processing it is possible to realize conical nanoneedles (nN) with controlled length, apical and basal diameter, density and porosity^[4]. These nanoneedles can interface with cells either from the bottom (nN-B), by seeding the cells over them or from the top (nN-T) by pressing them over the cells. In both instances the nanoneedles interface with the cell cytosol without inducing toxicity and enable intracellular delivery and sensing. The cell-nanoneedle interface evolves over time, with cells progressively descending along the needles, which come in close proximity to the nucleus, deforming it^[5]. Eventually the either the nanoneedles degrade (nN-B) or they are forcefully removed (nN-B) and cytosolic interfacing is lost. For the duration of the interfacing the nanoneedles are capable of both delivering payload to the cell and sensing the intracellular environment, regardless of interfacing strategy. Nanoneedles can efficiently deliver DNA and siRNA payloads to over 90% of the cells being interfaced, capable respectively of expressing and silencing genes^[4]. The delivery of hVEFG165 DNA to the muscle of mouse in vivo results in the sustained expression of the human VEGF protein for over a week, leading to the formation of new blood vessels resulting in a six-fold increase in local blood perfusion. Similarly nanoneedles can mediate the delivery of nanoparticles to the cell cytosol, bypassing the endolysosomal system^[5]. Such direct delivery enables the presentation of quantum dots within cells both in culture and in a small animal model. Differently from topical administration of nanoparticles, their nanoinjection results in highly localized and prolonged retention for up to 100h. The nanoinjection delivery mechanism is highly biocompatible and minimally invasive. Nanoinjection to skin, ear and muscle of mouse did not display any sign of alteration to tissue structure at the micro and nanoscale, neither on the impacted surface nor in the bulk of the tissue. Furthermore no sign of acute or chronic inflammation, such as cell necrosis, infiltration of immune cells or formation of granulation tissue, were observed in the context of nanoinjection^[4]. In summary, mesoporous silicon nanoneedles demonstrate the ability to efficiently deliver a broad range of therapeutic agents within cells, both in vitro and in vivo, with minimal invasiveness and elevated biocompatibility, enabling highly localized treatment. Such ability testifies to the potential of nanoneedles for clinical translation in the context of tissue engineering and the treatment of chronic, degenerative diseases. References [1] R. Elnathan, M. Kwiat, F. Patolsky, N. H. Voelcker, Nano Today 2014, 9, 172. [2] C. Chiappini, in Handbook of Porous Silicon, Springer International Publishing, Cham, 2014, pp. 171–186. [3] C. Chiappini, X. Liu, J. R. Fakhoury, M. Ferrari, Adv. Funct. Mater. 2010, 20, 2231. [4] C. Chiappini, E. De Rosa, J. O. Martinez, X. Liu, J. Steele, M. M. Stevens, E. Tasciotti, Nat Mater 2015, 14, 532. [5] C. Chiappini, J. O. Martinez, E. De Rosa, C. S. Almeida, E. Tasciotti, M. M. Stevens, ACS Nano 2015, 150417133816003.