A Customized Biohybrid Presenting Cascade Responses to Tumor Microenvironment.

Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts, and uncontrolled proliferation constrain their exploitation in medical applications such as tumor therapy. Here, the authors report an engineered biohybrid that can efficiently target cancerous sites through a pre-determined metabolic pathway to enable precise tumor ablation. In this system, DH5α Escherichia coli is engineered by the introduction of hypoxia-inducible promoters and lactate oxidase genes, and further surface-armored with iron-doped ZIF-8 nanoparticles. This bioengineered E. coli can produce and secrete lactate oxidase to reduce lactate concentration in response to hypoxic tumor microenvironment, as well as triggering immune activation. The peroxidase-like functionality of the nanoparticles extends the end product of the lactate metabolism, enabling the conversion of hydrogen peroxide (H2O2) into highly cytotoxic hydroxyl radicals. This, coupled with the transformation of tirapazamine loaded on nanoparticles to toxic benzotriazinyl, culminates in severe tumor cell ferroptosis. Intravenous injection of this biohybrid significantly inhibits tumor growth and metastasis.

Cobalt-based hybrid nanoparticles loaded with curcumin for ligand-enhanced synergistic nanocatalytic therapy/chemotherapy combined with calcium overload.

The therapeutic efficacy of Fenton or Fenton-like nanocatalysts is usually restricted by the inappropriate pH value and limited concentration of hydrogen peroxide (H2O2) at the tumor site. Herein, calcium carbonate (CaCO3)-mineralized cobalt silicate hydroxide hollow nanocatalysts (CSO@CaCO3, CC) were synthesized and loaded with curcumin (CCC). This hybrid system can simultaneously realize nanocatalytic therapy, chemotherapy and calcium overload. With the stabilization of liposomes, CCC is able to reach the tumor site smoothly. The CaCO3 shell first degrades in an acidic tumor environment, releasing Cur and Ca2+, and the pH value of the tumor is increased simultaneously. Then the exposed CSO catalyzes the Fenton-like reaction to convert H2O2 into ˙OH and enhances the cytotoxicity of curcumin (Cur) by catalytically oxidizing it to a ˙Cur radical. Curcumin not only induces the chemotherapy effect but also serves as a nucleophilic ligand and an electron donor in the catalytic system, enhancing the Fenton-like activity of CCC by electron transfer. In addition, calcium overload also amplifies the efficacy of ROS-based therapy. In vitro and in vivo results show that CCC exhibited an excellent synergistic tumor inhibition effect without any clear side effect. This work proposes a novel concept of nanocatalytic therapy/chemotherapy synergistic mechanism by the ligand-induced enhancement of Fenton-like catalytic activity, and inspires the construction of combined therapeutic nanoplatforms and multifunctional nanocarriers for drug and ion delivery in the future.

Hollow CoFe Nanozymes Integrated with Oncolytic Peptides Designed via Machine-Learning for Tumor Therapy.

Developing novel substances to synergize with nanozymes is a challenging yet indispensable task to enable the nanozyme-based therapeutics to tackle individual variations in tumor physicochemical properties. The advancement of machine learning (ML) has provided a useful tool to enhance the accuracy and efficiency in developing synergistic substances. In this study, ML models to mine low-cytotoxicity oncolytic peptides are applied. The filtering Pipeline is constructed using a traversal design and the Autogluon framework. Through the Pipeline, 37 novel peptides with high oncolytic activity against cancer cells and low cytotoxicity to normal cells are identified from a library of 25,740 sequences. Combining dataset testing with cytotoxicity experiments, an 80% accuracy rate is achieved, verifying the reliability of ML predictions. Peptide C2 is proven to possess membranolytic functions specifically for tumor cells as targeted by Pipeline. Then Peptide C2 with CoFe hollow hydroxide nanozyme (H-CF) to form the peptide/H-CF composite is integrated. The new composite exhibited acid-triggered membranolytic function and potent peroxidase-like (POD-like) activity, which induce ferroptosis to tumor cells and inhibits tumor growth. The study suggests that this novel ML-assisted design approach can offer an accurate and efficient paradigm for developing both oncolytic peptides and synergistic peptides for catalytic materials.

Integration of CoAl-Layered Double Hydroxides on Commensal Bacteria to Enable Targeted Tumor Inhibition and Immunotherapy.

Combining targeted therapy and immunotherapy brings hope for a complete cancer cure. Due to their selective colonization and immune activation capacity, some bacteria have the potential to realize targeted immunotherapy. Herein, a biohybrid system was designed and synthesized by cladding NO3--intercalated cobalt aluminum layered double hydroxides (LDH) on anaerobic Propionibacterium acnes (PA) (PA@LDH). In this system, the covering of LDH reduces the pathogenicity of PA to normal tissues and alters its surface charge for prolonged in vivo circulation. Once the tumor site is reached, the acid-responsive degradation of LDH enables PA exposure. PA can colonize and convert nitrate ions to nitric oxide (NO) through denitrification. Then, NO reacts with intracellular O2·- to produce toxic reactive nitrogen species ONOO- and induce tumor cell apoptosis. In addition, cobalt ions released from LDH can inhibit the activity of superoxide dismutase (SOD), thus increasing the level of O2·- and further enhancing the antitumor effect. Moreover, PA exposure activates M2-to-M1 macrophage polarization and a range of immune responses, thereby achieving a sustained antitumor activity. In vitro and in vivo results reveal that the biohybrid system eliminates solid tumors and inhibits tumor metastasis effectively. Overall, the biohybrid strategy provides a new avenue for realizing simultaneous immunotherapy and targeted therapy.

An Alternative Thinking in Tumor Therapeutics: Living Yeast Armored with Silicate.

A hybrid platform, constructed via the surface "armoring" of living yeasts by a manganese silicate compound (MS@Yeast), is investigated for combinational cancer treatment. The intrinsic characteristics of living yeasts, in both acidophilic and anaerobic conditions, empower the hybrid platform with activated selected colonization in tumors. While silicate particles are delivered in a targeting manner, yeast fermentation occurs at the cancerous region, inducing both alcohol and CO2. The excessive content of alcohol causes the hemangiectasis of tumor tissue, facilitating the penetration of therapeutics into central tumors and subsequent endocytosis. The catalytic Mn2+ ions, released from silicate particles, react with CO2 to induce forceful oxidative stress in tumor cells, ablating the primary tumors. More interestingly, the debris of sacrificed tumor cells and yeasts triggers considerable antitumor immune responses, rejecting both rechallenged and metastatic tumors. The integration of biologically active microorganisms and functional materials, illustrated in this study, provides distinctive perspectives in the exploration of potential therapeutics for tackling cancer.

An Inter-Cooperative Biohybrid Platform to Enable Tumor Ablation and Immune Activation.

A biohybrid therapeutic system, consisting of responsive materials and living microorganisms with inter-cooperative effects, is designed and investigated for tumor treatment. In this biohybrid system, S2 O3 2- -intercalated CoFe layered double hydroxides (LDH) are integrated at the surface of Baker's yeasts. Under the tumor microenvironment, functional interactions between yeast and LDH are effectively triggered, resulting in S2 O3 2- release, H2 S production, and in-situ generation of highly catalytic agents. Meanwhile, the degradation of LDH in the tumor microenvironment induces the exposure of the surface antigen of yeast, leading to effective immune activation at the tumor site. By virtue of the inter-cooperative phenomena, this biohybrid system exhibits significant efficacy in tumor ablation and strong inhibition of recurrence. This study has potentially offered an alternative concept by utilizing the metabolism of living microorganisms and materials in exploring effective tumor therapeutics.

A bifunctional bortezomib-loaded porous nano-hydroxyapatite/alginate scaffold for simultaneous tumor inhibition and bone regeneration.

Treatments of osteolytic lesions due to malignant metastasis remain one of the major clinical challenges. The residual tumor cells after surgical resections and an acidic tumor microenvironment are unfavorable for osteogenic induction. Bortezomib (BTZ), a proteasome inhibitor used in chemotherapy, also has an osteogenic potential in concentration- and Ca2+-dependent manners. In this study, controlled delivery of BTZ in a novel bifunctional scaffold based on nano-hydroxyapatite (nHA) and sodium alginate (SA) nanocomposite, namely BTZ/nHA@SA, has been explored. By smartly adjusting microenvironments, a sustainable release of Ca2+ from nHA could be achieved, which was not only able to cross-link SA but also to regulate the switch between the dual functions of tumor inhibition and bone regeneration of BTZ to promote the osteogenic pathway. The freeze-dried BTZ/nHA@SA scaffold has excellent interconnectivity, is capable to promote the attachment and proliferation of mouse embryonic osteoblast precursor cells, as well as effectively induces breast cancer cell death in vitro. Furthermore, in vivo, studies using a mouse tumor model and a rabbit femoral defect model showed that the BTZ/nHA@SA scaffold could promote tumor ablation, and also enhance bone repair. Therefore, the BTZ/nHA@SA scaffold has unique dual functions of inhibiting tumor recurrence and promoting bone tissue regeneration simultaneously. This smart bi-functional scaffold offers a promising novel approach for oncological treatments by synchronously orchestrating tumor inhibition and tissue regeneration for the repair of neoplastic bone defects.

An implantable composite scaffold for amplified chemodynamic therapy and tissue regeneration.

Tissue regeneration and tumor cell killing after surgical resection are the two keys to achieving effective tumor therapy. In this study, an implantable system with combined functions of tumor therapy and tissue repair was constructed. Tannic acid (TA)/Fe3+ nanoparticles with Fenton catalytic activity were loaded with GSH inhibitor BSO drug (BTF), and acted as the therapeutic factor to realize amplified chemodynamic tumor treatment. Bioactive glass (BG) fibers loaded with vascular endothelial growth factor (VEGF) were used as the drug carrier matrix with tissue repair function (BGV). Then the BGV@BTF composite fibers were obtained by anchoring BTF nanoparticles on the surface of BGV fibers. Under tumorous acidic conditions, BTF nanoparticles can be released from the composite fibers, and taken up by tumor cells. Facilitated by BSO with the GSH suppression effect and TA with Fe3+ reducing properties, BTF nanoparticles can realize high oxidative stress in tumor cells and subsequent cell death. In addition, BG fibers and VEGF can both promote tissue regeneration and accelerate postoperative wound healing. The simultaneous suppression of tumor growth and promotion of tissue repair in this work is inspiring in the field of postoperative tumor treatment and recovery.

Integration of Silica Nanorattles with Manganese-Doped In2S3/InOOH to Enable Ultrasound-Mediated Tumor Theranostics.

As a result of their radiation-free nature and deep-penetration ability, tumor theranostics mediated by ultrasound have become increasingly recognized as a modality with high potential for translation into clinical cancer treatment. The effective integration of ultrasound imaging and sonodynamic therapy (SDT) into one nanoplatform remains an enormous challenge yet to be fully resolved. Here, a novel theranostic system, consisting of rattle-type SiO2 (r-SiO2) loaded with Mn-doped In2S3/InOOH (SMISO), was designed and synthesized to enable an improved ultrasound imaging-guided therapy. With Mn-doped In2S3/InOOH (MISO) and a heterojunction structure, this novel sonosensitizer facilitates the generation of reactive oxygen species (ROS) for SDT. By coupling interfaces between the shell and core in rattle-type SiO2, multiple reflections/scattering are generated, while MISO has high acoustic impedance. By integrating r-SiO2 and MISO, the SMISO composite nanoparticles (NPs) increase the acoustic reflection and provide enhanced contrast for ultrasound imaging. Through the effective accumulation in tumors, which was monitored by B-mode ultrasound imaging in vivo, SMISO composite NPs effectively inhibited tumor growth without adverse side effects under ultrasound irradiation treatment. This work therefore provides a new approach to integrate a novel gas-free ultrasound contrast agent and a semiconductor sonosensitizer for cancer theranostics.

KCl-CaCO3 nanoclusters armoured with Pt nanocrystals for enhanced electro-driven tumor inhibition.

Electrodynamic therapy (EDT) has recently emerged as an alternative approach for tumor therapy via the generation of ROS by platinum (Pt) nanoparticles under electric field. An interesting phenomenon observed during EDT is that the increased on-site concentration of chloride ions is highly beneficial for ROS generation and inhibition efficacy. Here, in this study, nanoclusters (KCC), consisting of potassium chloride (KCl) nanocrystals and amorphous calcium carbonate (CaCO3), were synthesized and integrated with platinum nanoparticles (KCCP). In this system, KCC can dissolve and release calcium and chloride ions within tumor cells. The intracellular chloride ions considerably facilitated ROS generation by Pt nanoparticles under an electric field. More importantly, the excessive calcium ions and ROS formed a cycle of mutual promotion and self-amplification in cells, leading to agitated tumor inhibition, both in vitro and in vivo.

α-Fe2O3@Pt heterostructure particles to enable sonodynamic therapy with self-supplied O2 and imaging-guidance.

Sonodynamic therapy (SDT), presenting spatial and temporal control of ROS generation triggered by ultrasound field, has attracted considerable attention in tumor treatment. However, its therapeutic efficacy is severely hindered by the intrinsic hypoxia of solid tumor and the lack of smart design in material band structure. Here in study, fine α-Fe2O3 nanoparticles armored with Pt nanocrystals (α-Fe2O3@Pt) was investigated as an alternative SDT agent with ingenious bandgap and structural design. The Schottky barrier, due to its unique heterostructure, suppresses the recombination of sono-induced electrons and holes, enabling superior ROS generation. More importantly, the composite nanoparticles may effectively trigger a reoxygenation phenomenon to supply sufficient content of oxygen, favoring the ROS induction under the hypoxic condition and its extra role played for ultrasound imaging. In consequence, α-Fe2O3@Pt appears to enable effective tumor inhibition with imaging guidance, both in vitro and in vivo. This study has therefore demonstrated a highly potential platform for ultrasound-driven tumor theranostic, which may spark a series of further explorations in therapeutic systems with more rational material design.

Modeling and Research on an Immuno-Epidemiological Coupled System with Coinfection.

In this paper, a two-strain model with coinfection that links immunological and epidemiological dynamics across scales is formulated. On the with-in host scale, the two strains eliminate each other with the strain having the larger immunological reproduction number persisting. However, on the population scale coinfection is a common occurrence. Individuals infected with strain one can become coinfected with strain two and similarly for individuals originally infected with strain two. The immunological reproduction numbers [Formula: see text], the epidemiological reproduction numbers [Formula: see text] and invasion reproduction numbers [Formula: see text] are computed. Besides the disease-free equilibrium, there are strain one and strain two dominance equilibria. The disease-free equilibrium is locally asymptotically stable when the epidemiological reproduction numbers [Formula: see text] are smaller than one. In addition, each strain dominance equilibrium is locally asymptotically stable if the corresponding epidemiological reproduction number is larger than one and the invasion reproduction number of the other strain is smaller than one. The coexistence equilibrium exists when all the reproduction numbers are greater than one. Simulations suggest that when both invasion reproduction numbers are smaller than one, bistability occurs with one of the strains persisting or the other, depending on initial conditions.

Catalytic core-shell nanoparticles with self-supplied calcium and H2O2 to enable combinational tumor inhibition.

Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo.

Hollow ferric-tannic acid nanocapsules with sustained O2 and ROS induction for synergistic tumor therapy.

Nanoparticles presenting promoted catalytic activity, oxygen induction and loading capability are in high demand for effective synergistic tumor therapy. Herein, ferric-tannic acid complex nanocapsules with fine hollow microstructure (HFe-TA) are synthesized and loaded with a photosensitizer (indocyanine green, ICG) for synergistic tumor therapy. In acidic environment, ICG@HFe-TA decomposes and releases Fe3+ ions, TA and ICG molecules. Fe3+, with low catalytic activity, is effectively converted into highly catalytic Fe2+ by the reductant TA, enabling promoted efficacy of ˙OH induction. More importantly, the ROS (1O2) induction by ICG is significantly enhanced under 808 nm laser irradiation due to the O2 byproduct of Fe3+/Fe2+ conversion. In consequence, the ICG@HFe-TA nanoparticles exhibit considerable in vitro and in vivo tumor inhibition owing to the combined effect of ˙OH and 1O2 induced intracellularly. This study has therefore demonstrated a potential platform enabling combined photodynamic and chemodynamic therapy with high efficacy.

Biodegradable MnFe-hydroxide nanocapsules to enable multi-therapeutics delivery and hypoxia-modulated tumor treatment.

Developing drug delivery platforms that can modulate a tumor microenvironment and deliver multiple therapeutics to targeted tumors is critical for efficient cancer treatment. Achieving these platforms still remains a great challenge. Herein, biodegradable nanocapsules based on MnFe hydroxides (H-MnFe(OH)x) have been developed as a new type of cargo delivery with high loading capacity and catalytic activity, enabling synergetic therapy with promoted efficacy by relieving hypoxia in tumor tissues. As a proof of concept, a photosensitizer (indocyanine green, ICG) and a chemotherapeutic drug (doxorubicin, DOX) are co-loaded in nanocapsules and selectively released upon degradation of the nanocapsules in the acidic tumor microenvironment, and are promoted by near infrared irradiation. Meanwhile, Mn2+/Fe3+ ions released from the degradation of nanocapsules catalyze the conversion of H2O2 in a tumor microenvironment into oxygen, which modulates tumor hypoxia and dramatically boosts multimodal therapies. Remarkable synergistic anticancer outcomes have been demonstrated both in vitro and in vivo, paving the way towards future multifunctional therapeutic platforms.

Implantable fibrous 'patch' enabling preclinical chemo-photothermal tumor therapy.

Localized drug delivery systems (LDDSs), in the forms of fibers or hydrogel, have emerged as an alternative approach for effective cancer treatment, but suffer challenges in the limited efficacy originated from sole therapeutic functionality. Herein, a multifunctional LDDS, showing feasibility for minimally-invasive implantation, was designed and synthesized for on-site chemo-photothermal synergistic therapy. In this system, polydopamine (PDA) nanoparticles, loaded with doxorubicin (DOX), were assembled at the surface of electrospun PCL-gelatin (PG) fibers (PG@PDA-DOX). The composite PG@PDA-DOX nanofibers could effectively transform NIR light into heat and present excellent photostability. In addition, low pH and NIR irradiation enabled remarkably accelerated DOX release. The in vitro study of PG@PDA-DOX fibers showed effective anti-cancer effect with irradiation of 808 nm NIR by inducing cell apoptosis and suppressing cell proliferation. The in vivo study, by implanting PG@PDA-DOX nanofibers in the patient derived xenograft (PDX) model via minimally-invasive surgery, presented that the composite fibers can effectively inhabit tumor growth by the combined chemo-photothermal effect without clear systematic side-effects. This study has therefore demonstrated a minimally-invasive platform, in a fibrous mesh form, with both high therapeutic efficacy and considerable potential in clinical translation for liver cancer treatment.

Multifunctional Electrospun Nanofibers for Enhancing Localized Cancer Treatment.

Localized cancer treatment is one of the most effective strategies in clinical destruction of solid tumors at early stages as it can minimize the side effects of cancer therapeutics. Electrospun nanofibers have been demonstrated as a promising implantable platform in localized cancer treatment, enabling the on-site delivery of therapeutic components and minimizing side effects to normal tissues. This Review discusses the recent cutting-edge research with regard to electrospun nanofibers used for various therapeutic approaches, including gene therapy, chemotherapy, photodynamic therapy, thermal therapy, and combination therapy, in enhancing localized cancer treatment. Furthermore, it extensively analyzes the current challenges and potential breakthroughs in utilizing this novel platform for clinical transition in localized cancer treatment.

Upconversion nanocrystal 'armoured' silica fibres with superior photoluminescence for miRNA detection.

We have fabricated a flexible membrane, consisting of SiO2 nanofibres armoured with upconversion nanoparticles, exhibiting intense photoluminescence. These assemblies were subsequently grafted with molecular beacons to produce a biosensor suitable for the detection of specific microRNA and with applications in early cancer detection and point-of-care diagnosis.

A Bifunctional Scaffold for Tissue Regeneration and Photothermal Therapy.

Clinical treatment for cancer comprises surgical removal and chemo/radio-therapy. In general, surgical intervention causes large defects while chemo/radio-therapy brings drug resistance and long-term suffering to patients. Major challenges remain in developing a therapeutic platform for simultaneous cancer treatment and tissue regeneration. In this study, a bifunctional scaffold based on gold nanorods-conjugated bioactive glass (BG@GNR) nanofibers was investigated for this purpose. Owing to gold nanoparticles anchored at the surface of nanofibers, the composite scaffold exhibits excellent photothermal effect. Under 808 nm near-infrared (NIR) irradiation for 5 minutes, the temperature of scaffold reaches ∼42.5 °C which induced more than 89.5% cancer cell death. Meanwhile, the scaffold can effectively promote the proliferation of epithelial cells by 270% after 72 h incubation, confirming its expected bioactivity. The findings suggested that the BG@GNR scaffold holds a promise for localized photothermal therapy and tissue regeneration, which is specifically inspiring in treating tumor-induced defects.

Enhanced cell uptake of fluorescent drug-loaded nanoparticles via an implantable photothermal fibrous patch for more effective cancer cell killing.

Great efforts have been devoted to effective delivery of therapeutics into cells for cancer therapy. The exploration of nanoparticle based drug delivery systems (DDSs) faces daunting challenges in low efficacy of intracellular delivery. Herein, a localized drug delivery device consisting of photoluminescent mesoporous silica nanoparticles (PLMSNs) and photothermal fibrous matrix was investigated. Specifically, PLMSNs modified with a pH-sensitive polydopamine (PDA) 'gatekeeper' served as a doxorubicin (DOX) carrier and could release DOX once the PLMSNs were up-taken by the cancer cells. The PLMSNs were electrostatically assembled on the surface of electrospun biodegradable poly(ε-caprolactone)/gelatin fibrous mesh incorporated with photothermal carbon nanoparticles (CNPs), leading to an implantable patch used as localized delivery platform. Comparing to free particulate DDSs, this implantable composite patch device was found to significantly enable superior cell up-taking effect and consequently enhance in-vitro therapeutic efficacy against tumor cells. Namely, under near infrared irradiation, the photothermal effect of CNPs in the implantable patch weakens the electrostatic interaction between the PLMSNs and poly(ε-caprolactone)/gelatin/CNP fibrous mesh, resulting in the controlled release of the PLMSNs and subsequent internalization into the tumor cells for more effective cancer cell killing. This implantable therapeutic device may therefore inspire another way of developing localized cancer therapy.