Nanozyme-based catalytic tumor therapy is an emerging therapeutic method with high reactivity in response to tumor microenvironments (TMEs). To overcome the current limitations of deficient catalytic activity of nanozymes, we studied the contributing factors of enzymatic activity based on non-metallic-atom doping and irradiation. Nitrogen doping significantly enhanced the peroxidase activity of Ti-based nanozymes, which was shown experimentally and theoretically. Based on the excellent NIR-adsorption-induced surface plasmon resonance and photothermal effect, the enzymatic activity of TiN nanoparticles (NPs) was further improved under NIR laser irradiation. Hence, an acidic TME-responsive and irradiation-mediated cascade nanocatalyst (TLGp) is presented by using TiN-NP-encapsulated liposomes linked with pH-responsive PEG-modified glucose oxidase (GOx). The integration of pH-responsive GOx-mediated H2 O2 self-supply, nitrogen-doping, and irradiation-enhanced enzymatic activity of TiN NPs and mild-photothermal therapy enables an effective tumor inhibition by TLGp with minimal side effects in vivo.

A Titanium Nitride Nanozyme for pH-Responsive and Irradiation-Enhanced Cascade-Catalytic Tumor Therapy.

Multi-drug resistance (MDR) in cancer cells, either intrinsic or acquired through various mechanisms, significantly hinders the therapeutic efficacy of drugs. Typically, the reduced therapeutic performance of various drugs is predominantly due to the inherent over expression of ATP-binding cassette (ABC) transporter proteins on the cell membrane, resulting in the deprived uptake of drugs, augmenting drug detoxification, and DNA repair. In addition to various physiological abnormalities and extensive blood flow, MDR cancer phenotypes exhibit improved apoptotic threshold and drug efflux efficiency. These severe consequences have substantially directed researchers in the fabrication of various advanced therapeutic strategies, such as co-delivery of drugs along with various generations of MDR inhibitors, augmented dosage regimens and frequency of administration, as well as combinatorial treatment options, among others. In this review, we emphasize different reasons and mechanisms responsible for MDR in cancer, including but not limited to the known drug efflux mechanisms mediated by permeability glycoprotein (P-gp) and other pumps, reduced drug uptake, altered DNA repair, and drug targets, among others. Further, an emphasis on specific cancers that share pathogenesis in executing MDR and effluxed drugs in common is provided. Then, the aspects related to various nanomaterials-based supramolecular programmable designs (organic- and inorganic-based materials), as well as physical approaches (light- and ultrasound-based therapies), are discussed, highlighting the unsolved issues and future advancements. Finally, we summarize the review with interesting perspectives and future trends, exploring further opportunities to overcome MDR. 

Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges.

Metal-organic frameworks (MOF) have been studied for infinite applications. Among these, anticancer therapy has surely attracted great interest due to the intrinsic characteristics of MOFs: large surface area, tuneable porosity, remarkable biocompatibility, easy production, and the possibility to further functionalize the realized nanoparticles are the main reasons that make MOFs the ideal candidates to overcome traditional chemotherapy limits and resistance. Smart MOFs are becoming particularly relevant, as they can be activated by specific endogenous or exogenous stimuli and release their cargo only under the selected conditions. Tumor microenvironment (TME) offers the possibility to take advantage of its peculiar composition to design and build smart nanoparticles, able to selectively release the therapeutic payload only in the environment surrounding cancer cells or directly in the intracellular environment. In this review, we have summarized novel and innovative works describing anticancer MOF-based nanoparticles loaded with biomolecules published in the last three years. The reported papers have been selected with special focus on TME-responsive MOFs and the synthetic procedures employed by research groups have been reported for almost all works, to further underline the myriad of possibilities offered by these hybrid metal-organic structures.

Metal-organic frameworks (MOFs) as biomolecules drug delivery systems for anticancer purposes.

With the changing disease spectrum, atherosclerosis has become increasingly prevalent worldwide and the associated diseases have emerged as the leading cause of death. Due to their fascinating physical, chemical, and biological characteristics, nanomaterials are regarded as a promising tool to tackle enormous challenges in medicine. The emerging discipline of nanomedicine has filled a huge application gap in the atherosclerotic field, ushering a new generation of diagnosis and treatment strategies. Herein, based on the essential pathogenic contributors of atherogenesis, as well as the distinct composition/structural characteristics, synthesis strategies, and surface design of nanoplatforms, the three major application branches (nanodiagnosis, nanotherapy, and nanotheranostic) of nanomedicine in atherosclerosis are elaborated. Then, state-of-art studies containing a sequence of representative and significant achievements are summarized in detail with an emphasis on the intrinsic interaction/relationship between nanomedicines and atherosclerosis. Particularly, attention is paid to the biosafety of nanomedicines, which aims to pave the way for future clinical translation of this burgeoning field. Finally, this comprehensive review is concluded by proposing unresolved key scientific issues and sharing the vision and expectation for the future, fully elucidating the closed loop from atherogenesis to the application paradigm of nanomedicines for advancing the early achievement of clinical applications.

Nanomedicine for Diagnosis and Treatment of Atherosclerosis.

Effective tumor treatment depends on optimizing drug penetration and accumulation in tumor tissue while minimizing systemic toxicity. Nanomedicine has emerged as a key solution that addresses the rapid clearance of free drugs, but achieving deep drug penetration into solid tumors remains elusive. This review discusses various strategies to enhance drug penetration, including manipulation of the tumor microenvironment, exploitation of both external and internal stimuli, pioneering nanocarrier surface engineering, and development of innovative tactics for active tumor penetration. One outstanding strategy is organelle-affinitive transfer, which exploits the unique properties of specific tumor cell organelles and heralds a potentially transformative approach to active transcellular transfer for deep tumor penetration. Rigorous models are essential to evaluate the efficacy of these strategies. The patient-derived xenograft (PDX) model is gaining traction as a bridge between laboratory discovery and clinical application. However, the journey from bench to bedside for nanomedicines is fraught with challenges. Future efforts should prioritize deepening our understanding of nanoparticle-tumor interactions, re-evaluating the EPR effect, and exploring novel nanoparticle transport mechanisms. 

Enhancing drug penetration in solid tumors via nanomedicine: Evaluation models, strategies and perspectives

The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumor glycolysis, which leads to the accumulation of lactic acid and promotes tumor metastasis. In order to increase tumor penetration, it remains challenging to avoid tumor metastasis by the direct degradation of the extracellular matrix (ECM). Herein, in order to increase tumor penetration, a nano-platform, which can reduce extracellular matrix (ECM) production, and inhibit the glycolysis of deep tumors by releasing ethylenediaminetetraacetic acid (EDTA) is reported. In this design, EDTA and indocyanine green (ICG) are encapsulated in the liposome by a thin-film hydration method, and folic acid (FA) and the polyethyleneimine polymer (FA-PEI) are applied to coat the surface of liposomes through electrostatic interactions, and the FA-EDTA/ICG-Lip nanoparticles are obtained. FA-EDTA/ICG-Lip NPs can release EDTA and ICG in lysosomes (pH 4.5) to reduce ECM production by down-regulating transforming growth factor β (TGF-β) and activating an immune response by inducing tumor cell immunogenic cell death (ICD), respectively. Simultaneously, EDTA inhibits glycolysis of deep tumors by chelating Mg2+. By avoiding tumor metastasis, the strategy of indirectly reducing ECM production is demonstrated to enhance tumor penetration and inhibit deep tumor glycolysis.

A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer.

With the existing medical diagnostic technology, the diagnosis of atherosclerosis (AS) is mainly focused on the later stage of AS development rather than plaque imaging in the period before plaque formation. It is impractical to apply the existing theoretical methods for the purpose of early detection of AS. Herein, this study uses a naphthalimide-based fluorescent probe for recognition of cellular reactive oxygen species (ROS). A platelet membrane (Mp) with foam cell targeting was wrapped around the probes to prepare two vesicle structures TBNG@Mp and GNTB@Mp. The animal experiment results show that the screened nano-detection system TBNG@Mp could accumulate in the thoracic aorta of early AS rats. Under the effect of intracellular ROS, fluorescence signals can be observed. In addition, acute biological toxicity was not observed in pathological sections. Therefore, the foam cell targeting system TBNG@Mp with acceptable biocompatibility can realize the detection of AS one to two decades in advance as well as has a good application prospect.

A nano-detection system based on a chemical probe for early diagnosis of atherosclerosis in situ

The poor penetration of solid tumors hinders the development of hunger therapy represented by glucose oxidase (GOx). To address this limitation, we have constructed a GOx/Dex@ZIF-TA nanosystem consisting of tannic acid (TA), carrier ZIF-8, encapsulated GOx and dexamethasone (Dex). In this nanosystem, the loaded Dex can not only expand the pores of the nucleus to promote GOx to enter the nucleus, addressing the shortcomings of short life of reactive oxygen species, but also inhibit the production of collagen to reshape the tumor microenvironment and inhibit lung metastasis. In vivo experiments proved that Dex could inhibit the production of collagen, which increased the accumulation and penetration of the tumor tissues and inhibited lung metastasis. In addition, cell experiments showed that Dex could also enlarge the nuclear pores of the nucleus and promote the entry of drugs into the nucleus. More importantly, Dex is a broad anti-inflammatory drug, and the results of this study should be easily transformed to achieve clinical benefits. Together, this work provided a way to address the limitations of hunger distribution in tumor tissues.

Reshaping the tumor microenvironment for increasing the distribution of glucose oxidase in tumor and inhibiting metastasis

Foam cell formation and further accumulation in the subendothelial space of the vascular wall is a hallmark of early atherosclerosis (AS). Targeting foam cell formation can be a promising approach for the early detection and prevention of AS. However, only a few studies have actually examined foam cells in vivo, and most methods combined nanotechnology with angiography, which is complex and could cause further damage to the endothelium. Herein, based on methylene blue, a biosafe NIR dye approved by the FDA, an interventional probe (HMB-NA@Mp) triggered by hypochlorous acid (HClO) was designed for imaging foam cells easily, safely, and effectively in the early stage of AS. Here, encapsulation of the probe by foam cells targeted platelet membrane (Mp) increased probe targeting and reduced toxicity. Cell and animal experimental results showed that the probe could accumulate at the lesion site and significantly enhance fluorescence in the early AS model group. Remarkably, at the same time, it could also release the metabolite niacin, which played a role in inhibiting atherosclerosis. Thus, HMB-NA@Mp is expected to be a powerful means for the early detection and timely intervention of early AS in the absence of clinical symptoms.

HClO-triggered interventional probe enabled early detection and intervention of atherosclerosis.

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A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer.

A nano-detection system based on a chemical probe for early diagnosis of atherosclerosis in situ

Reshaping the tumor microenvironment for increasing the distribution of glucose oxidase in tumor and inhibiting metastasis

HClO-triggered interventional probe enabled early detection and intervention of atherosclerosis.