Cancer has been one of the most common life‐threatening diseases for a long time. Traditional cancer therapies such as surgery, chemotherapy (CT), and radiotherapy (RT) have limited effects due to drug resistance, unsatisfactory treatment efficiency, and side effects. In recent years, photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) have been utilized for cancer treatment owing to their high selectivity, minor resistance, and minimal toxicity. Accumulating evidence has demonstrated that selective delivery of drugs to specific subcellular organelles can significantly enhance the efficiency of cancer therapy. Mitochondria‐targeting therapeutic strategies are promising for cancer therapy, which is attributed to the essential role of mitochondria in the regulation of cancer cell apoptosis, metabolism, and more vulnerable to hyperthermia and oxidative damage. Herein, the rational design, functionalization, and applications of diverse mitochondria‐targeting units, involving organic phosphine/sulfur salts, quaternary ammonium (QA) salts, peptides, transition‐metal complexes, guanidinium or bisguanidinium, as well as mitochondria‐targeting cancer therapies including PDT, PTT, CDT, and others are summarized. This review aims to furnish researchers with deep insights and hints in the design and applications of novel mitochondria‐targeting agents for cancer therapy.

A novel pH- and redox- dual-responsive tumor-triggered targeting mesoporous silica nanoparticle (TTTMSN) is designed as a drug carrier. The peptide RGDFFFFC is anchored on the surface of mesoporous silica nanoparticles via disulfide bonds, which are redox-responsive, as a gatekeeper as well as a tumor-targeting ligand. PEGylated technology is employed to protect the anchored peptide ligands. The peptide and monomethoxypolyethylene glycol (MPEG) with benzoic-imine bond, which is pH-sensitive, are then connected via "click" chemistry to obtain TTTMSN. In vitro cell research demonstrates that the targeting property of TTTMSN is switched off in normal tissues with neutral pH condition, and switched on in tumor tissues with acidic pH condition after removing the MPEG segment by hydrolysis of benzoic-imine bond under acidic conditions. After deshielding of the MPEG segment, the drug-loaded nanoparticles are easily taken up by tumor cells due to the exposed peptide targeting ligand, and subsequently the redox signal glutathione in tumor cells induces rapid drug release intracellularly after the cleavage of disulfide bond. This novel intelligent TTTMSN drug delivery system has great potential for cancer therapy.

Fibronectin 1 (FN1) is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, metastasis, and implicated in various biochemical processes. However, its effects on the development and progression of human cancer, especially colorectal cancer (CRC), are unclear. To evaluate the relationship between the expression of FN1 and the histopathologic parameters of patients with CRC or the proliferation, migration, and invasion of colorectal cancer cell lines, we screened FN1 as a new candidate gene which promotes development of CRC, in an independent dataset (The Human Protein Atlas website). Here, we reported that FN1 was elevated in CRC tissues compared with normal colon tissues. Further, FN1 expression level was correlated with age, lymph vascular invasion, and survival rate. Knockdown of FN1 in two CRC cell lines, LOVO, and SW1116, significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Western blot analysis showed that down-regulation of FN1 significantly decreased the expression of Bcl-2, MMP-9, Twist, and increased the expression of Bax, Caspase-3, and E-cadherin in LOVO and SW1116 cells. Then, we found that the protein ITGA5 was identified as a binding partner of FN1 and ITGA5 overexpression reversed FN1-induced tumorigenesis of CRC in vitro. Taken together, FN1 suppressed apoptosis and promoted viability, invasion, and migration in CRC through interacting with ITGA5. FN1 may be a prognostic factor and potential target for CRC treatment.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor (S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano-Pt) as a catalase-like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano-Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano-Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed "nano-Pt/VP@MLipo," is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano-Pt catalyzation improves the VP-mediated PDT, which in turn triggers the release of nano-Pt via membrane permeabilization. The ultrasmall 3-5 nm nano-Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano-Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.