Engineering Stealth Properties of Fluorescent Polymeric Nanoparticles by Short‐Chain Polysarcosine

The stealth properties of nanoparticles (NPs) constitute key parameters controlling colloidal stability and nonspecific interactions, which are critical for biological applications. To address the limitations of polyethylene glycol (PEG), commonly used for this purpose, we investigate polysarcosine (PSar) peptoid to determine the shortest chain length required to confer stealth properties to NPs. Polymeric NPs encapsulating rhodamine dye with a bulky hydrophobic counterion and bearing azide groups at their surface are functionalized by click chemistry with PSar of different lengths, ranging from 5 to 19 sarcosine units. The obtained peptoid‐functionalized NPs show remarkable colloidal stability in physiological media, in contrast to bare polymeric NPs. An increase in the length of grafted PSar results in a reduction of the negative surface charge to near‐neutral values and diminishes protein adsorption and aggregation in blood serum, as evidenced by fluorescence correlation spectroscopy. NPs grafted with 19‐mer PSar show minimal nonspecific interactions with live cells and glass surfaces in a complex biological media, in contrast to their shorter PSar analogues and bare polymeric NPs. The developed stealth NPs bearing 19‐mer PSar and HaloTag ligand enable specific targeting and imaging of proteins at the cell surface with minimized nonspecific interactions. The obtained results suggest that a relatively short PSar peptoid can be used for achieving stealth properties in polymeric NPs, allowing fabrication of the next‐generation nanomaterials for bioimaging and biosensing applications. We foresee that the use of optimized short‐chain PSar as a stealth shell could be extended to other types of functional nanomaterials, which can improve their safety, surface chemistry, and performance.