Reversibly Extracellular pH Controlled Cellular Uptake and Photothermal Therapy by PEGylated Mixed-Charge Gold Nanostars

Shielding nanoparticles from nonspecific interactions with normal cells/tissues before they reach and after they leave tumors is crucial for the selective delivery of NPs into tumor cells. By utilizing the reversible protonation of weak electrolytic groups to pH changes, long‐chain amine/carboxyl‐terminated polyethylene glycol (PEG) decorated gold nanostars (GNSs) are designed, exhibiting reversible, significant, and sensitive response in cell affinity and therapeutic efficacy to the extracellular pH (pHe) gradient between normal tissues and tumors. This smart nanosystem shows good dispersity and unimpaired photothermal efficacy in complex bioenvironment at pH 6.4 and 7.4 even when their surface charge is neutral. One PEGylated mixed‐charge GNSs with certain surface composition, GNS‐N/C 4, exhibits high cell affinity and therapeutic efficacy at pH 6.4, and low affinity and almost “zero” damage to cells at pH 7.4. Remarkably, this significant and sensitive response in cell affinity and therapeutic efficacy is reversible as local pH alternated. In vivo, GNS‐N/C 4 shows higher accumulation in tumors and improved photothermal therapeutic efficacy than pH‐insensitive GNSs. This newly developed smart nanosystem, whose cell affinity reversibly transforms in response to pHe gradient with unimpaired biostability, provides a novel effective means of tumor‐selective therapy. Reversible pHe control: PEGylated mixed‐charge gold nanostars are synthesized for reversibly extracellular pH controlled (pHe) photothermal therapy. The pH‐reversible protonation of these gold nanostars may translate into adjustable degree of cellular uptake, and enable tumor‐targeted photothermal therapy under dynamic control.