Two‐Stage Size Decrease and Enhanced Photoacoustic Performance of Stimuli‐Responsive Polymer‐Gold Nanorod Assembly for Increased Tumor Penetration

A promising theranostic platform for solid tumors would deliver and release anticancer nanomedicine effectively in tumor cells. However, diverse biological barriers, especially related to the tumor microenvironment, impede these theranostic agents from reaching the tumor cell. Herein, a sequential pH and reduction‐responsive polymer and gold nanorod (AuNR) core–shell assembly to overcome these barriers via a two‐stage size decrease and disassembly of the nanoplatform responding to the specified tumor microenvironment are reported. The tumor uptake of the hybrid nanoparticle (NP) is 14.2% ID g−1, which is two and four times higher than the noneresponsive hybrid NPs and small AuNR@PEG, respectively. After tumor uptake of the hybrid NPs, the disassembled ultrasmall AuNRs coated with a polymer of polymerized reduction‐responsive doxorubicin (DOX) prodrug monomers penetrate into the solid tumor and lead to localized DOX release in the tumor cell. A linear increase in photoacustic (PA) effects from the PA activating polymer on an AuNR cluster surface indicates a critical role of electromagnetic fields in the AuNR assembly, which is consistent with the theoretical calculation results. Furthermore, the hybrid NP can serve as a promising deep‐tissue PA and surface‐enhanced Raman scattering imaging agent for real‐time in vivo investigation of physiological behaviors and deep tumor penetrating nanotherapy effects. A novel polymer and ultrasmall gold nanorod (AuNR) core–shell assembly with sequential pH‐ and reduction‐responsive abilities and amplified photoacoustic performance is developed to overcome the inherent barriers in the tumor region via a two‐stage size decrease and disassembly of the nanoplatform responding to the specified tumor microenvironment of pH and reduction, thus leading to enhanced tumor penetration efficacy.