Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed‐loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS‐induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue.     

Biomarker-Responsive Nanosystems for Chronic Disease Theranostics

Chronic diseases claim millions of lives every year, and it is of great significance to explore and develop advanced drugs to improve the cure rate of chronic diseases. Nanotheranostics are innovative strategies that enable the integration of diagnostic and therapeutic properties into a single nanosystem. Despite great success in nanotheranostics, their applications of nanotheranostics in nanomedicine are still in their infancy. This is because each disease has its corresponding characteristic pathological microenvironment, which motivates the development of endogenous biomarker-responsive nanosystems to meet the requirements of diagnosis and treatment. Herein, recent progress is presented in biomarker-responsive nanosystems and their biomedical applications. First, biomarker-responsive nanosystems are classified into eight subsections according to the type of chronic diseases, including tumors, cardiovascular diseases, neurological diseases, Wilson's diseases, chronic liver diseases, chronic kidney diseases, diabetes mellitus, and rheumatoid arthritis. In the following, a variety of intriguing applications of biomarkers-responsive nanosystems are briefly elaborated, such as biosensing, diagnosis, therapy, combined theranostics, and early evaluation of therapy effect, etc. Finally, the challenges and future directions from research to clinical translation of these responsive nanosystems are also presented.     

Tailoring crystal facet microenvironments for simultaneous electrochemical ozone and hydrogen peroxide production

Developing a bifunctional electrocatalyst that can effectively produce O₃ and H₂O₂ is significant for the electrochemical synthesis of O₃ and H₂O₂ for the synergistic oxidative degradation of organic pollutants. In this study, SnO with various exposed facets was synthesized by tailoring the crystal facet microenvironment for oxygen intermediates adsorption for electrochemical ozone production (EOP) and two-electron oxygen reduction reaction (2e⁻ ORR). The Faraday efficiency of SnO-1 with a high (110) facet ratio for O₃ was 22.0%, while SnO-4 with a high (002) facet ratio achieved a selectivity of 93.6% for H₂O₂. The theoretical calculation indicates that their excellent performances originated from the strong adsorption of the (110) facet on O* and O₂* and the suitable adsorption and desorption strength of the (002) facet on OOH*, respectively. This study provides an attractive strategy for the development of a bifunctional electrocatalyst for advanced electrochemical oxidation by tailoring the crystal facet microenvironment.     

A Versatile Pt‐Based Core–Shell Nanoplatform as a Nanofactory for Enhanced Tumor Therapy

Hypoxia, one of the representative characteristics in solid tumors, not only reduces the effectiveness of multiple treatments, but also relates to the tumor invasion and metastasis. Here, a hybrid core–shell nanoplatform to produce adequate oxygen, supporting for more effective tumor treatment, is developed. Composed of polydopamine cores, platinum nanoparticle interlayers, and zirconium‐porphyrin (PCN) shells, the hybrid core–shell nanoplatform works like a nanofactory, providing necessary products at different time and space. Platinum nanoparticle interlayers can catalyze the endogenous H₂O₂ to O₂, which plays a dual rule in the enhanced tumor treatment. In the presence of light irradiation, O₂ can be converted into the lethal reactive oxygen species by the PCN shell. In the absence of light irradiation, O₂ ameliorates the hypoxic microenvironment, thereby reduces the invasion and metastasis of the tumor. Through a synergism of enhanced treatment and reduced metastasis, tumors could be treated more vigorously.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

High-Throughput Magnetic Actuation Platform for Evaluating the Effect of Mechanical Force on 3D Tumor Microenvironment

Accurately replicating and analyzing cellular responses to mechanical cues is vital for exploring metastatic disease progression. However, many of the existing in vitro platforms for applying mechanical stimulation seed cells on synthetic substrates. To better recapitulate physiological conditions, a novel actuating platform is developed with the ability to apply tensile strain on cells at various amplitudes and frequencies in a high-throughput multi-well culture plate using a physiologically relevant substrate. Suspending fibrillar fibronectin across the body of the magnetic actuator provides a matrix representative of early metastasis for 3D cell culture that is not reliant on a synthetic substrate. This platform enables the culturing and analysis of various cell types in an environment that mimics the dynamic stretching of lung tissue during normal respiration. Metabolic activity, YAP activation, and morphology of breast cancer cells are analyzed within one week of cyclic stretching or static culture. Further, matrix degradation is significantly reduced in breast cancer cell lines with metastatic potential after actuation. These new findings demonstrate a clear suppressive cellular response due to cyclic stretching that has implications for a mechanical role in the dormancy and reactivation of disseminated breast cancer cells to macrometastases.