Stimuli-responsive ferroptosis for cancer therapy.

Ferroptosis, an iron-dependent programmed cell death mechanism, is regulated by distinct molecular pathways of lipid peroxidation caused by intracellular iron supplementation and glutathione (GSH) synthesis inhibition. It has attracted a great deal of attention as a viable alternative to typical apoptosis-based cancer therapy that exhibits drug resistance. For efficient therapeutic utilization of such a unique and desirable mechanism, precise control using various stimuli to activate the administered nanocarriers is essential. Specific conditions in the tumor microenvironment (e.g., acidic pH, high level of ROS and GSH, hypoxia, etc.) can be exploited as endogenous stimuli to ensure high specificity of the tumor site. Maximized spatiotemporal controllability can be assured by utilizing external energy sources (e.g., magnetic fields, ultrasound, microwaves, light, etc.) as exogenous stimuli that can provide on-demand remote controllability for customized deep tumor therapy with a low inter-patient variation. Strikingly, the utilization of dual endogenous and/or exogenous stimuli provides a new direction for efficient cancer therapy. This review highlights recent advances in the utilization of various endogenous and exogenous stimuli to activate the reactions of nanocarriers for ferroptosis-based cancer therapy that can inspire the field of cancer therapy, particularly for the treatment of intractable tumors.

Cancer therapeutics based on diverse energy sources.

Light-based phototherapy has been developed for cancer treatment owing to its non-invasiveness and spatiotemporal control. Despite the unique merits of phototherapy, one critical disadvantage of light is its limited penetration depth, which restricts its application in cancer treatment. Although many researchers have developed various strategies to deliver light into deep-seated tumors with two-photon and near-infrared light irradiation, phototherapy encounters the peculiar limitations of light. In addition, high oxygen dependency is another limitation of photodynamic therapy to treat hypoxic tumors. To overcome the drawbacks of conventional treatments, various energy sources have been developed for cancer treatment. Generally, most energy sources, such as ultrasound, chemiluminescence, radiation, microwave, electricity, and magnetic field, are relatively free from the restraint of penetration depth. Combining other strategies or therapies with other energy-source-based therapies improves the strength and compensates for the weakness. This tutorial review focuses on recent advances in the diverse energy sources utilized in cancer treatment and their future perspectives.

Nanolayered hybrid mediates synergistic co-delivery of ligand and ligation activator for inducing stem cell differentiation and tissue healing.

Cellular behaviors, such as differentiation, are regulated by complex ligation processes involving cell surface receptors, which can be activated by various divalent metal cations. The design of nanoparticle for co-delivery of ligand and ligation activator can offer a novel strategy to synergistically stimulate ligation processes in vivo. Here, we present a novel layered double hydroxide (LDH)-based nanohybrid (MgFe-Ado-LDH), composed of layered MgFe hydroxide nanocarriers sandwiching the adenosine cargo molecule, maintained through an electrostatic balance, to co-deliver the adenosine (Ado) ligand from the interlayer spacing and the Mg2+ ion (ligation activator) through the dissolution of the MgFe nanocarrier itself. Our findings demonstrate that the MgFe-Ado-LDH nanohybrid promoted osteogenic differentiation of stem cells through the synergistic activation of adenosine A2b receptor (A2bR) by the dual delivery of adenosine and Mg2+ ions, outperforming direct supplementation of adenosine alone. Furthermore, the injection of the MgFe-Ado-LDH nanohybrid and stem cells embedded within hydrogels promoted the healing of rat tibial bone defects through the rapid formation of fully integrated neo-bone tissue through the activation of A2bR. The newly formed bone tissue displayed the key features of native bone, including calcification, mature tissue morphology, and vascularization. This study demonstrates a novel and effective strategy of bifunctional nanocarrier-mediated delivery of ligand (cargo molecule) and activation of its ligation to receptor by the nanocarrier itself for synergistically inducing stem cell differentiation and tissue healing in vivo, thus offering novel design of biomaterials for regenerative medicine.

Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells.

The physical and chemical properties of a matrix play an important role in determining various cellular behaviors, including lineage specificity. We demonstrate that the differentiation commitment of human embryonic stem cells (hESCs), both in vitro and in vivo, can be solely achieved through synthetic biomaterials. hESCs were cultured using mineralized synthetic matrices mimicking a calcium phosphate (CaP)-rich bone environment differentiated into osteoblasts in the absence of any osteogenic inducing supplements. When implanted in vivo, these hESC-laden mineralized matrices contributed to ectopic bone tissue formation. In contrast, cells within the corresponding non-mineralized matrices underwent either osteogenic or adipogenic fate depending upon the local cues present in the microenvironment. To our knowledge, this is the first demonstration where synthetic matrices are shown to induce terminal cell fate specification of hESCs exclusively by biomaterial-based cues both in vitro and in vivo. Technologies that utilize tissue specific cell-matrix interactions to control stem cell fate could be a powerful tool in regenerative medicine. Such approaches can be used as a tool to advance our basic understanding and assess the translational potential of stem cells.