in combination with adjuvant chemotherapy is commonly applied at the early stage of cancer, but subsequent relapse and metastasis always lead to a poor clinical outcome. During cancer metastasis, sentinel lymph nodes (SLNs) near the tumors are usually the first site through which the cancer cells spread to lung, liver and other vital organs. [1] To address these challenges, great efforts have been devoted to developing novel anticancer drugs and nanosized drug delivery systems for suppressing both primary tumor growth and lymphatic metastasis.Protein degradation has become an attractive target for chemotherapy. Ubiquitin-proteasome system (UPS) and autophagy are two major routes responsible for the degradation of intracellular proteins and organelles. [2] More than 80% of cellular proteins including misfolded and damaged proteins are cleaned by UPS. Disruption of protein homeostasis by inhibition of proteasome attenuates multiple signaling pathways involved in tumor transformation. [3] Bortezomib and carfilzomib (CFZ) are the first-and second-generation of clinically approved proteasome inhibitors, respectively. [4] Due to the poor aqueous solubility of CFZ, sulfobutyl ether β-cyclodextrin as a solubilizer is needed to make CFZ injectable. Recently, The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.

Transarterial chemoembolization (TACE) is commonly used for treating advanced hepatocellular carcinoma (HCC). However, the instability of lipiodol-drug emulsion and the altered tumor microenvironment (TME, such as hypoxia-induced autophagy) postembolization are responsible for the unsatisfactory therapeutic outcomes. Herein, pH-responsive poly(acrylic acid)/calcium phosphate nanoparticles (PAA/CaP NPs) were synthesized and used as the carrier of epirubicin (EPI) to enhance the efficacy of TACE therapy through autophagy inhibition. PAA/CaP NPs have a high loading capacity of EPI and a sensitive drug release behavior under acidic conditions. Moreover, PAA/CaP NPs block autophagy through the dramatic increase of intracellular Ca2+ content, which synergistically enhances the toxicity of EPI. TACE with EPI-loaded PAA/CaP NPs dispersed in lipiodol shows an obvious enhanced therapeutic outcome compared to the treatment with EPI-lipiodol emulsion in an orthotopic rabbit liver cancer model. This study not only develops a new delivery system for TACE but also provides a promising strategy targeting autophagy inhibition to improve the therapeutic effect of TACE for the HCC treatment.

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