Photothermal therapy (PTT) is an emerging therapeutic strategy in the treatment of cancer; however, a critical challenge remains in the rational design of synergistic nanoparticles as potential photothermal transduction agent that can effectively enhance the therapeutic outcome of PTT for tumor ablation. Herein, we rationally designed, developed, and characterized hollow-structured CuS nanoparticles composited with carbon dots (CuSCD), which demonstrated excellent photothermal conversion efficiency under 808 nm laser irradiation with enhanced biocompatibility and reduced toxicity. Following coating macrophage membrane hybridized with T7 peptide on the surface of proteasome inhibitor loaded CuSCD, CuSCDB@MMT7 exhibited targeted specificity to cancer cells with the characteristics of immune escaping and enhanced transferrin receptormediated endocytosis. Predominantly, CuSCDB@MMT7-triggered PTT exhibited the accumulation of polyubiquitinated tumor suppressor protein that is heat stabilized under NIR induced hyperthermia, facilitating augmented tumor cell apoptosis and the attenuated metastasis.This study provides a proof-of-concept for the proteasome inhibitor-loaded CuS/carbon dots nanocomposites-PTT strategy, and highlights a promising therapeutic strategy for realizing enhanced therapeutic outcomes for effective clinical cancer therapy. KEYWORDS: photothermal therapy, carbon dots, CuS nanoparticles, bortezomib, polyubiquitinated proteins Photothermal therapy (PTT) is a minimally invasive and potentially effective therapeutic modality that is capable of eliminating a variety of cancer types. 1 PTT is essentially the ablation of tumor through localized hyperthermia achieved by utilizing photothermal effect of photothermal transduction agents (PTAs), which converts optical energy into thermal energy upon irradiation Page 2 of 48 ACS Paragon Plus Environment ACS Nano 3with light. 2,3 However, the major challenge to PTT is the limited photothermal conversion efficiency (PCE) of photothermal transduction agents (PTAs), which may lead to inefficient and incomplete ablation of the entire tumors on irradiation. 4,5 In particular, a barrier is that the minimum laser power intensity for effective PTT is still significantly higher than the conservative limit for human skin exposure. Improving the PCE and reducing the laser power density has become a direction for the development of PTT. Owing to the high PCE, enhanced photothermal stability, versatility, and ease of synthesis and surface modification, inorganic or its hybrid materials have been extensively used as the PTAs. 6 However, in addition to the reported potential toxicity of some inorganic agents, their poor stability in the physiological condition, low drug loading capacity, low biodegradability, and compositions complexity may impede their metabolism resulting in their long-time accumulation in the body, thus these drawbacks have limited their clinical applications. 7 To address these limitations, studies have been devoted by various research groups for the inve...