Invented in the 1990s, near-field optical microscopy (NSOM) was the first optical microscopy method to hold the promise of finally breaking the diffraction barrier in studies of biological samples. This promise, though, failed to materialize at that time, largely owing to the inability to image soft samples, such as cell surfaces, without damage. However, steady technical improvements have now produced NSOM devices that can routinely achieve images of cell surfaces with sub-100 nm resolution in aqueous solution. Further, beyond just optical information, these instruments can also provide simultaneous topographic, mechanical, and/or chemical details of the sample, an ability not yet matched by any other optics-based methodology. With the long recognized important roles of many biological processes at cell surfaces in human health and disease, near-field probing of cell surfaces is indeed now well poised to directly illume in biomedicine what has, until recently, been unknowable with classic light microscopy.From the Clinical EditorThis paper presents a novel and important near-field microscopy-based method directly enabling the imaging of cell surfaces with sub-100nm resolution. Unlike other optics-based methods, the presented technique can also provide topographic, mechanical and chemical details of the samples.

The transport of molecules and ions across nanometer-scaled pores, created by natural or artificial molecules, is a phenomenon of both fundamental and practical significance. Biological channels are the most remarkable examples of mass transport across membranes and demonstrate nearly exclusive selectivity and high efficiency with a diverse collection of molecules. These channels are critical for many basic biological functions, such as membrane potential, signal transduction, and osmotic homeostasis.If such highly specific and efficient mass transport or separa tion could be achieved with artificial nanostructures under controlled conditions, they could create revolutionary technologies in a variety of areas. For this reason, investigators from diverse disciplines have vigorously studied small nondeformable nanopores. The most exciting studies have focused on carbon nanotubes (CNTs), which have exhibited fast mass transport and high ion selectivity despite their very simple structure. However, the limitations of CNTs and the dearth of other small (≤2 nm) nanopores have severely hampered the systematic investigation of nanopore-mediated mass transport, which will be essential for designing artificial nanopores with desired functions en masse.Researchers can overcome the difficulties associated with CNT and other artificial pores by stacking macrocyclic building blocks with persistent shapes to construct tunable, self-assembling organic pores. This effort started when we discovered a highly efficient, one-pot macrocyclization process to efficiently prepare several classes of macrocycles with rigid backbones containing nondeformable cavities. Such macrocycles, if stacked atop one another, should lead to nanotubular assemblies with defined inner pores determined by their constituent macrocycles. One class of macrocycles with aromatic oligoamide backbones had a very high propensity for directional assembly, forming nanotubular structures containing nanometer and sub-nanometer hydrophilic pores. These self-assembling hydrophilic pores can form ion channels in lipid membranes with very large ion conductances.To control the assembly, we have further introduced multiple hydrogen-bonding side chains to enforce the stacking of rigid macrocycles into self-assembling nanotubes. This strategy has produced a self-assembling, sub-nanometer hydrophobic pore that not only acted as a transmembrane channel with surprisingly high ion selectivity, but also mediated a significant transmembrane water flux.The stacking of rigid macrocycles that can be chemically modified in either the lumen or the exterior surface can produce self-assembling organic nanotubes with inner pores of defined sizes. The combination of our approach with the availability and synthetic tunability of various rigid macrocycles should produce a variety of organic nanopores. Such structures would allow researchers to systematically explore mass transport in the sub-nanometer regime. Further advances should lead to novel applications such as biosensing, materials separation, and molecular purifications.