Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

Discovery of 5-(Pyrimidin-2-ylamino)-1H-indole-2-carboxamide Derivatives as Nur77 Modulators with Selective and Potent Activity Against Triple-Negative Breast Cancer.

The orphan nuclear receptor Nur77 has been validated as a potential drug target for treating breast cancer. Therefore, focusing on the SAR study of the lead 8b (KDSPR(Nur77) = 354 nM), we found the active compound ja which exhibited improved Nur77-binding capability (KDSPR(Nur77) = 91 nM) and excellent antiproliferative activities against breast cancer cell lines. Interestingly, ja acted as a potent and selective Nur77 antagonist, displaying good potency against triple-negative breast cancer (TNBC) cell lines but did not inhibit human normal breast cancer cell line MCF-10A (SI > 20). Exceptionally, ja Nur77-dependently caused mitochondria dysfunction and induced the caspase-dependent apoptosis by mediating the TP53 phosphorylation pathway. Moreover, ja significantly suppressed MDA-MB-231 xenograft tumor growth but had no apparent side effects in mice and zebrafish. Overall, ja demonstrated to be the first Nur77 modulator mediating the TP53 phosphorylation pathway that has the potential as a novel anticancer agent for TNBC.

Virus-like particles nanoreactors: from catalysis towards bio-applications.

Virus-like particles (VLPs) are self-assembled supramolecular structures found in nature, often used for compartmentalization. Exploiting their inherent properties, including precise nanoscale structures, monodispersity, and high stability, these architectures have been widely used as nanocarriers to protect or enrich catalysts, facilitating catalytic reactions and avoiding interference from the bulk solutions. In this review, we summarize the current progress of virus-like particles (VLPs)-based nanoreactors. First, we briefly introduce the physicochemical properties of the most commonly used virus particles to understand their roles in catalytic reactions beyond the confined space. Next, we summarize the self-assembly of nanoreactors forming higher-order hierarchical structures, highlighting the emerging field of nanoreactors as artificial organelles and their potential biomedical applications. Finally, we discuss the current findings and future perspectives of VLPs-based nanoreactors.

Ultrasound meets the cell membrane: for enhanced endocytosis and drug delivery.

Endocytosis plays a crucial role in drug delivery for precision therapy. As a non-invasive and spatiotemporal-controllable stimulus, ultrasound (US) has been utilized for improving drug delivery efficiency due to its ability to enhance cell membrane permeability. When US meets the cell membrane, the well-known cavitation effect generated by US can cause various biophysical effects, facilitating the delivery of various cargoes, especially nanocarriers. The comprehension of recent progress in the biophysical mechanism governing the interaction between ultrasound and cell membranes holds significant implications for the broader scientific community, particularly in drug delivery and nanomedicine. This review will summarize the latest research results on the biological effects and mechanisms of US-enhanced cellular endocytosis. Moreover, the latest achievements in US-related biomedical applications will be discussed. Finally, challenges and opportunities of US-enhanced endocytosis for biomedical applications will be provided.

Transformable nanodrugs for overcoming the biological barriers in the tumor environment during drug delivery.

Drug delivery systems have been studied massively with explosive growth in the last few decades. However, challenges such as biological barriers are still obstructing the delivery efficiency of nanomedicines. Reports have shown that the physicochemical properties, such as the morphologies of nanodrugs, could highly affect their biodistribution and bioavailability. Therefore, transformable nanodrugs that take advantage of different sizes and shapes allow for overcoming multiple biological barriers, providing promising prospects for drug delivery. This review aims to present an overview of the most recent developments of transformable nanodrugs in this emerging field. First, the design principles and transformation mechanisms which serve as guidelines for smart nanodrugs are summarized. Afterward, their applications in overcoming biological barriers, including the bloodstream, intratumoral pressure, cellular membrane, endosomal wrapping, and nuclear membrane, are highlighted. Finally, discussions on the current developments and future perspectives of transformable nanodrugs are given.

Carbonic anhydrase IX-targeted nanovesicles potentiated ferroptosis by remodeling the intracellular environment for synergetic cancer therapy.

Ferroptosis is one critical kind of regulated cell death for tumor suppression, yet it still presents challenges of low efficiency due to the intracellular alkaline pH and aberrant redox status. Herein, we reported a carbonic anhydrase IX (CA IX)-targeted nanovesicle (PAHC NV) to potentiate ferroptosis by remodeling the intracellular environment. CA IX inhibitor 4-(2-aminoethyl) benzene sulfonamide (AEBS) was anchored onto nanovesicles loaded with hemoglobin (Hb) and chlorin e6 (Ce6). Upon reaching tumor regions, PAHC could be internalized by cancer cells specifically by means of CA IX targeting and intervention. Afterwards, the binding of AEBS could elicit intracellular acidification and alter redox homeostasis to boost the lipid peroxidation (LPO) level, thus aggravating the ferroptosis process. Meanwhile, Hb served as an iron reservoir that could efficiently evoke ferroptosis and release O2 to ameliorate tumor hypoxia. With the help of self-supplied O2, Ce6 produced a plethora of 1O2 for enhanced photodynamic therapy, which in turn favored LPO accumulation to synergize ferroptosis. This study presents a promising paradigm for designing nanomedicines to heighten ferroptosis-based synergetic therapeutics through remodeling the intracellular environment.

Activation of Antibiotic-Grafted Polymer Brushes by Ultrasound.

The ultrasound-mediated activation of drugs from macromolecular architectures using the principles of polymer mechanochemistry (sonopharmacology) is a promising strategy to gain spatiotemporal control over drug activity. Yet, conceptual challenges limit the applicability of this method. Especially low drug-loading content and low mechanochemical efficiency require the use of high carrier mass concentrations and prolonged exposure to ultrasound. Moreover, the activated drug is generally shielded by the hydrodynamic coil of the attached polymer fragment leading to a decreased drug potency. Here we present a carrier design for the ultrasound-induced activation of vancomycin, which is deactivated with its H-bond-complementary peptide target sequence. We show that the progression from mechanophore-centered linear chains to mechanophore-decorated polymer brushes increases drug-loading content, mechanochemical efficiency, and drug potency. These results may serve as a design guideline for future endeavors in the field of sonopharmacology.

Mechano-Nanoswitches for Ultrasound-Controlled Drug Activation.

Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote-controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US-controlled drug activation strategy, herein a mechano-responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof-of-concept, the synthesis, characterization, and US-responsive drug activation evaluation of the mechano-nanoswitch, which provides a blueprint for tailoring nanosystems for force-induced pharmacotherapy is presented.

Virus-inspired nanosystems for drug delivery.

With over millions of years of evolution, viruses can infect cells efficiently by utilizing their unique structures. Similarly, the drug delivery process is designed to imitate the viral infection stages for maximizing the therapeutic effect. From drug administration to therapeutic effect, nanocarriers must evade the host's immune system, break through multiple barriers, enter the cell, and release their payload by endosomal escape or nuclear targeting. Inspired by the virus infection process, a number of virus-like nanosystems have been designed and constructed for drug delivery. This review aims to present a comprehensive summary of the current understanding of the drug delivery process inspired by the viral infection stages. The most recent construction of virus-inspired nanosystems (VINs) for drug delivery is sorted, emphasizing their novelty and design principles, as well as highlighting the mechanism of these nanosystems for overcoming each biological barrier during drug delivery. A perspective on the VINs for therapeutic applications is provided in the end.

Reversible regulation of metallo-base-pair interactions for DNA dehybridization by ultrasound.

Mechanical force applied by ultrasound in solution leads to the dissociation of DNA metallo-base-pair interactions when these motifs are functionalized with oligodeoxynucleotide sequences of sufficient length. The annealing and force-induced denaturing process is followed by the attachment of distance-sensitive fluorescent probes and is found to be reversible.

Activation of the Catalytic Activity of Thrombin for Fibrin Formation by Ultrasound.

The regulation of enzyme activity is a method to control biological function. We report two systems enabling the ultrasound-induced activation of thrombin, which is vital for secondary hemostasis. First, we designed polyaptamers, which can specifically bind to thrombin, inhibiting its catalytic activity. With ultrasound generating inertial cavitation and therapeutic medical focused ultrasound, the interactions between polyaptamer and enzyme are cleaved, restoring the activity to catalyze the conversion of fibrinogen into fibrin. Second, we used split aptamers conjugated to the surface of gold nanoparticles (AuNPs). In the presence of thrombin, these assemble into an aptamer tertiary structure, induce AuNP aggregation, and deactivate the enzyme. By ultrasonication, the AuNP aggregates reversibly disassemble releasing and activating the enzyme. We envision that this approach will be a blueprint to control the function of other proteins by mechanical stimuli in the sonogenetics field.

Gold-based nanomaterials for the treatment of brain cancer.

Brain cancer, also known as intracranial cancer, is one of the most invasive and fatal cancers affecting people of all ages. Despite the great advances in medical technology, improvements in transporting drugs into brain tissue have been limited by the challenge of crossing the blood-brain barrier (BBB). Fortunately, recent endeavors using gold-based nanomaterials (GBNs) have indicated the potential of these materials to cross the BBB. Therefore, GBNs might be an attractive therapeutic strategy against brain cancer. Herein, we aim to present a comprehensive summary of current understanding of the critical effects of the physicochemical properties and surface modifications of GBNs on BBB penetration for applications in brain cancer treatment. Furthermore, the most recent GBNs and their impressive performance in precise bioimaging and efficient inhibition of brain tumors are also summarized, with an emphasis on the mechanism of their effective BBB penetration. Finally, the challenges and future outlook in using GBNs for brain cancer treatment are discussed. We hope that this review will spark researchers' interest in constructing more powerful nanoplatforms for brain disease treatment.

Recent progress in mitochondria-targeting-based nanotechnology for cancer treatment.

Mitochondria play critical roles in the regulation of the proliferation and apoptosis of cancerous cells. Nanosystems for targeted delivery of cargos to mitochondria for cancer treatment have attracted increasing attention in the past few years. This review will summarize the state of the art of design and construction of nanosystems used for mitochondria-targeted delivery. The use of nanotechnology for cancer treatment through various pathways such as energy metabolism interference, reactive oxygen species (ROS) regulation, mitochondrial protein targeting, mitochondrial DNA (mtDNA) interference, mitophagy inducing, and combination therapy will be discussed. Finally, the major challenges and an outlook in this field will also be provided.

Mechanochemical bond scission for the activation of drugs.

Pharmaceutical drug therapy is often hindered by issues caused by poor drug selectivity, including unwanted side effects and drug resistance. Spatial and temporal control over drug activation in response to stimuli is a promising strategy to attenuate and circumvent these problems. Here we use ultrasound to activate drugs from inactive macromolecules or nano-assemblies through the controlled scission of mechanochemically labile covalent bonds and weak non-covalent bonds. We show that a polymer with a disulfide motif at the centre of the main chain releases an alkaloid-based anticancer drug from its ß-carbonate linker by a force-induced intramolecular 5-exo-trig cyclization. Second, aminoglycoside antibiotics complexed by a multi-aptamer RNA structure are activated by the mechanochemical opening and scission of the nucleic acid backbone. Lastly, nanoparticle-polymer and nanoparticle-nanoparticle assemblies held together by hydrogen bonds between the peptide antibiotic vancomycin and its complementary peptide target are activated by force-induced scission of hydrogen bonds. This work demonstrates the potential of ultrasound to activate mechanoresponsive prodrug systems.

Controlling Optical and Catalytic Activity of Genetically Engineered Proteins by Ultrasound.

Ultrasound (US) produces cavitation-induced mechanical forces stretching and breaking polymer chains in solution. This type of polymer mechanochemistry is widely used for synthetic polymers, but not biomacromolecules, even though US is biocompatible and commonly used for medical therapy as well as in vivo imaging. The ability to control protein activity by US would thus be a major stepping-stone for these disciplines. Here, we provide the first examples of selective protein activation and deactivation by means of US. Using GFP as a model system, we engineer US sensitivity into proteins by design. The incorporation of long and highly charged domains enables the efficient transfer of force to the protein structure. We then use this principle to activate the catalytic activity of trypsin by inducing the release of its inhibitor. We expect that this concept to switch "on" and "off" protein activity by US will serve as a blueprint to remotely control other bioactive molecules.

Ultrasound-controlled drug release and drug activation for cancer therapy.

Traditional chemotherapy suffers from severe toxicity and side effects that limit its maximum application in cancer therapy. To overcome this challenge, an ideal treatment strategy would be to selectively control the release or regulate the activity of drugs to minimize the undesirable toxicity. Recently, ultrasound (US)-responsive drug delivery systems (DDSs) have attracted significant attention due to the non-invasiveness, high tissue penetration depth, and spatiotemporal controllability of US. Moreover, the US-induced mechanical force has been proven to be a robust method to site-selectively rearrange or cleave bonds in mechanochemistry. This review describes the US-activated DDSs from the fundamental basics and aims to present a comprehensive summary of the current understanding of US-responsive DDSs for controlled drug release and drug activation. First, we summarize the typical mechanisms for US-responsive drug release and drug activation. Second, the main factors affecting the ultrasonic responsiveness of drug carriers are outlined. Furthermore, representative examples of US-controlled drug release and drug activation are discussed, emphasizing their novelty and design principles. Finally, the challenges and an outlook on this promising therapeutic strategy are discussed.

DNA hybridization as a general method to enhance the cellular uptake of nanostructures.

The biomedical application of nanoparticles (NPs) for diagnosis and therapy is considerably stalled by their inefficient cellular internalization. Many strategies to overcome this obstacle have been developed but are not generally applicable to different NP systems, consequently underlining the need for a universal method that enhances NP entry into cells. Here we describe a method to increase NP cellular uptake via strand hybridization between DNA-functionalized NPs and cells that bear the respective complementary sequence incorporated into the membrane. By this, the NPs bind efficiently to the cellular surface enhancing internalization of three completely different NP types: DNA tetrahedrons, gold (Au) NPs, and polystyrene (PS) NPs. We show that our approach is a simple and generalizable strategy that can be applied to virtually every functionalizable NP system.

Proton-driven transformable nanovaccine for cancer immunotherapy.

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.

Four-Dimensional Deoxyribonucleic Acid-Gold Nanoparticle Assemblies.

Organization of gold nanoobjects by oligonucleotides has resulted in many three-dimensional colloidal assemblies with diverse size, shape, and complexity; nonetheless, autonomous and temporal control during formation remains challenging. In contrast, living systems temporally and spatially self-regulate formation of functional structures by internally orchestrating assembly and disassembly kinetics of dissipative biomacromolecular networks. We present a novel approach for fabricating four-dimensional gold nanostructures by adding an additional dimension: time. The dissipative character of our system is achieved using exonuclease III digestion of deoxyribonucleic acid (DNA) fuel as an energy-dissipating pathway. Temporal control over amorphous clusters composed of spherical gold nanoparticles (AuNPs) and well-defined core-satellite structures from gold nanorods (AuNRs) and AuNPs is demonstrated. Furthermore, the high specificity of DNA hybridization allowed us to demonstrate selective activation of the evolution of multiple architectures of higher complexity in a single mixture containing small and larger spherical AuNPs and AuNRs.