The rational design of cancer‐targeted and bioresponsive drug delivery vehicles can enhance the anticancer efficacy of conventional chemotherapeutics and reduce their adverse side effects. However, the complexity of precise delivery and the ability to trigger drug release in specific tumor sites remain a challenging puzzle. Here, a sequentially triggered nanosystem composed of HER2 antibody with disulfide linkage as a surface decorator (HER2@NPs) is constructed for precise drug delivery and the simultaneous inhibition of cancer growth, migration, and invasion. The nanosystem actively accumulates in cancer cells, undergoes self‐immolative cleavage in response to biological thiols, and is degraded to form small nanoparticles. After internalization by receptor‐mediated endocytosis, the nanoparticles further disassemble under acidic conditions in the presence of lysozymes and cell lysates, leading to sequentially triggered drug release. The released payload triggers overproduction of reactive oxygen species and activates p53 and MAPKs pathways to induce cancer cell apoptosis. Moreover, HER2@NPs markedly suppress the migration and invasion of human bladder cancer cells at nontoxic concentrations. HER2@NPs demonstrate potent in vivo anticancer efficacy, but show no obvious histological damage to the major organs. Taken together, this study provides a valid tactic for the rational design of sequentially triggered nanosystems for precise drug delivery and cancer therapy.

Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a potent Ru polypyridyl complex (RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , bmbp=2,6-bis(6-methylbenzimidazol-2-yl) pyridine, phen=phenanthroline) with a chloride ligand, and revealed that aquation of RuBmp effectively enhanced its hydrophilicity and cellular uptake, thus significantly increasing its anticancer efficacy. The aquation products (H-RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , [Ru(II) (bmbp)(phen)(H2 O)]ClO4 , bmbp) exhibited a much higher apoptosis-inducing ability than the intact complex, with involvement of caspase activation, mitochondria dysfunction, and interaction with cell membrane death receptors. H-RuBmp demonstrated a higher interaction potency with the cell membrane and induced higher levels of ROS overproduction in cancer cells to regulate the AKT, MAPK, and p53 signaling pathways. Taken together, this study could provide useful information for fine-tuning the rational design of next-generation metal medicines.

The search for chemotherapeutic drugs with a high efficiency and low toxicity continues to be a challenge in tumor treatment for scientists. Organometallic supramolecular polymers are an attractive option to achieve this goal, not only due to the fact that they possess both advantages of metal complexes and nanostructures but also because they are usually sensitive to pH. Here, we report the design and synthesis of a series novel smart microenvironment-responsive organocopper­(II) supramolecular polymers with various substituted ligands to regulate their stability and anticancer efficacy. The investigation of the possible mechanisms revealed that the organocopper­(II) polymers enter cancer cells through endocytosis and then induce apoptosis of cancer cells. Furthermore, the in vivo anticancer efficacy study demonstrated that these organocopper­(II) polymers inhibited the tumor growth effectively without damage to the major organs. Overall, the organocopper­(II) supramolecular polymers present a promising pathway to achieve high-efficiency and low-toxicity chemotherapy.

Self‐assembled functional supramolecular metallopolymers have demonstrated application potential in cancer therapy. Herein, a copper polypyridyl complex was found able to self‐assemble into a supramolecular metallopolymer driven by the intermolecular interactions, which could enhance the uptake in cancer cells through endocytosis, and thus effectively inhibiting tumor growth in vivo without damaging to the major organs. This study provides a facile way to achieve enhanced anticancer efficacy by using self‐assembled metallopolymers.

A precise drug delivery system for simultaneously inhibiting cancer growth, migration, and invasion is presented by Tianfeng Chen and co‐workers on page 7775. The sequentially triggered nanosystem decorated by HER2 antibody with disulfide linkages provides a valid tactic for the rational design of smart nanosystems for drug delivery and therapy.