A Renally Excretable Gold Nanoparticle Oncology Platform Enabling Effective Photothermal Therapy and Chemotherapy Combination

Combination therapies have largely replaced monotherapies in oncology. Thermal therapy has been developed as an adjunctive treatment owing to its safety and high compatibility with established theraypy options. However, bulky equipment and non-standardized protocols have limited its clinical use. The emergence of gold nanoparticle (AuNP)-based photothermal therapy (PTT) offers a simpler approach using injectable formulations and portable near-infrared (NIR) laser devices. However, poor excretion of AuNPs raises safety concerns and hinders translation. Here, we designed a gold nanoplatform that retains the photothermal capacity of AuNPs while enabling efficient excretion. Ultrasmall AuNPs (<6 nm) with a hydrophilic coating may be renally cleared, but clustering normally alters biodistribution and results in long-term hepatic deposition, prior to excretion. In this study, we employed <i>p</i>-methoxybenzenethiol (MBT) to stabilize ultrasmall AuNPs, clustered them with poly-(lactic-<i>co</i>-glycolic acid) (PLGA), and coated said clusters with acetylated human serum albumin (Ac-HSA). The resulting Ac-HSA-PLGA-AuNCs demonstrated reduced hepatic retention along with renal excretion of ultrasmall gold species. Intratumoral injection followed by 10 min NIR irradiation achieved efficient tumor ablation, outperforming conventional hyperthermia that usually requires hours of heating. Furthermore, combining Ac-HSA-PLGA-AuNC-based PTT with high-dose paclitaxel (160 mg/kg) was safe and yielded enhanced antitumor efficacy. This developed gold nanoplatform offers a promising strategy for translatable PTT-chemotherapy combinations.