Considering the future clinical applications of localized cancer therapy, it is of great importance to construct injectable biodegradable nanocomposite hydrogels with combinatorial therapeutic efficacy. Here, porous silicon nanoparticles (PSiNPs) as host matrix were chosen to fabricate PSiNPs@Au nanocomposites via in situ reductive synthesis of gold nanoparticles. Then PSiNPs@Au nanocomposites were further incorporated into thermosensitive chitosan (CS) hydrogels to construct CS/PSiNPs@Au nanocomposite hydrogels, which showed in situ gelation at physiological temperature, excellent biodegradability, and biocompatibility. Especially with the encapsulation of CS hydrogels, PSiNPs@Au nanocomposites had a long-term stable photothermal effect with higher local temperature under near-infrared (NIR) laser irradiation, whether in vitro or in vivo. Besides, assisted by NIR laser irradiation, CS/PSiNPs@Au nanocomposite hydrogels exhibited a long-term sustained release of anticancer drugs (doxorubicin hydrochloride, DOX) in acidic tumor environments. Finally, DOX/CS/PSiNPs@Au precursors were administrated into tumor-bearing mice via a single intratumoral injection, which presented a significant synergistic chemo-photothermal therapeutic efficacy under repeated NIR laser irradiation during long-term cancer treatments. Accordingly, we developed a novel strategy to prepare multifunctional CS/PSiNPs@Au nanocomposite hydrogels and also demonstrated their potential applications in localized cancer therapy in future clinics.

Nanomedicines have been designed and developed to deliver anticancer drugs or exert anticancer therapy more selectively to tumor sites. Recent investigations have gone beyond delivering drugs to tumor tissues or cells, but to intracellular compartments for amplifying therapy efficacy. Mitochondria are attractive targets for cancer treatment due to their important functions for cells and close relationships to tumor occurrence and metastasis. Accordingly, multifunctional nanoplatforms have been constructed for cancer therapy with the modification of a variety of mitochondriotropic ligands, to trigger the mitochondria-mediated apoptosis of tumor cells. On this basis, various cancer therapeutic modalities based on mitochondria-targeted nanomedicines are developed by strategies of damaging mitochondria DNA (mtDNA), increasing reactive oxygen species (ROS), disturbing respiratory chain and redox balance. Herein, in this review, we highlight mitochondria-targeted cancer therapies enabled by nanoplatforms including chemotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT) and combined immunotherapy, and discussed the ongoing challenges.

Magnetic and photothermal PSiNPs@(Fe3O4/Au) nanocomposites as anticancer drug carriers improved combined chemo-photothermal therapeutic efficacy of drug-resistant breast cancer cells.

Recently, mitochondria-targeted photothermal nanoagents demonstrated an improved therapeutic efficacy of cancer cells, compared with non-targeting ones. Herein, copper sulfide (CuS) nanoparticles are in situ synthesized via bovine serum albumin (BSA) templates to prepare photothermal BSA@CuS nanocomposites with high efficiency (42.0%) of photothermal conversion. Subsequently, rhodamine-110 (R) molecules are covalently conjugated with BSA@CuS nanocomposites to construct mitochondria-targeted R-BSA@ CuS nanocomposites, which still retained 22.8% of photothermal conversion efficiency. Furthermore, as-prepared R-BSA@CuS nanocomposites can be efficiently internalized by human breast cancer (MCF-7) cells, and then specifically accumulated in their subcellular mitochondria, not lysosomes. Compared with non-targeting BSA@CuS nanocomposites, these mitochondria-targeted R-BSA@CuS nanocomposites show a significant enhancement (***p < 0.001) of their anticancer efficacy under the same near-infrared irradiation conditions, whose mechanism is further explored in details. Finally, these R-BSA@CuS nanocomposites can succeed in penetrating in 3D multicellular tumor spheroids composed of MCF-7 cells. And they also show a significant inhibition effect (**p < 0.01) on the growth of spheroids via photothermal therapy, in contrast to bare BSA@CuS nanocomposites under the same irradiation conditions. Therefore, these mitochondria-targeted and photothermal R-BSA@CuS nanocomposites have important potential applications on cancer photothermal therapy with an enhanced efficacy.

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