Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio–nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio–nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Fluorescence labelling is often used for tracking nanoparticles, providing a convenient assay for monitoring nanoparticle drug delivery. However, it is difficult to be quantitative, as many factors affect the fluorescence intensity. Förster resonance energy transfer (FRET), taking advantage of the energy transfer from a donor fluorophore to an acceptor fluorophore, provides a distance ruler to probe NP drug delivery. This article provides a review of different FRET approaches for the ratiometric monitoring of the self-assembly and formation of nanoparticles, their in vivo fate, integrity and drug release. We anticipate that the fundamental understanding gained from these ratiometric studies will offer new insights into the design of new nanoparticles with improved and better-controlled properties.