Dual‐Modality Detection of Intracellular Nanoparticles via Smart Polymer‐Enhanced SERS and Hyperspectral Microscopy Detection

Abstract Polymers are widely employed as surface coatings in nanotechnology to enhance the colloidal stability and solubility of nanoparticles (NPs). The choice of coating material is critical, as it influences the surface chemistry and potential applications of nanoparticles. In this study, a novel multidentate surfactant – 4‐mercaptoaniline‐methoxypolyoxyethyleneamine‐grafted‐poly(isobutylene‐ alt ‐maleic anhydride) (PAP) is developed – based on poly(isobutylene‐alt‐maleic anhydride) backbone with high affinity for metallic surfaces. This coating improves NP stability in aqueous solution by displacing excess surfactants – an often overlooked issue in nanomedicine affecting functionalization, cell viability, and molecular targeting in nanomedicine. Beyond stabilization, this multibranched surfactant exhibits an intrinsic ability to enhance Surface‐Enhanced Raman Scattering (SERS), making it a promising tool for biosensing and biomedical applications. These findings show that the SERS performance of nanoparticles coated with PAP is strongly dependent on key structural parameters, including their composition, size, morphology, and the excitation laser wavelength. Notably, concave cube gold nanoparticles exhibit superior SERS performance at 785 nm, highlighting their potential as theranostic agents. Furthermore, tracked NP internalization is successfully tracked in cancer cells by both hyperspectral and SERS microscopy, enabling precise detection of spherical gold NPs. These findings underscore the potential of the coating in advancing biosensing and nanomedicine.