Rational Design of Biomaterials to Potentiate Cancer Thermal Therapy.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

An Injectable Puerarin Depot Can Potentiate Chimeric Antigen Receptor Natural Killer Cell Immunotherapy Against Targeted Solid Tumors by Reversing Tumor Immunosuppression.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a potent approach to suppressing tumor growth because it has simultaneously inherited the specificity of CAR and the intrinsic generality of NK cells in recognizing cancer cells. However, its therapeutic potency against solid tumors is still restricted by insufficient tumor infiltration, immunosuppressive tumor microenvironments, and many other biological barriers. Motivated by the high potency of puerarin, a traditional Chinese medicine extract, in dilating tumor blood vessels, an injectable puerarin depot based on a hydrogen peroxide-responsive hydrogel comprising poly(ethylene glycol) dimethacrylate and ferrous chloride is concisely developed. Upon intratumoral fixation, the as-prepared puerarin depot (abbreviated as puerarin@PEGel) can activate nitrogen oxide production inside endothelial cells and thus dilate tumor blood vessels to relieve tumor hypoxia and reverse tumor immunosuppression. Such treatment can thus promote tumor infiltration, survival, and effector functions of customized epidermal growth factor receptor (HER1)-targeted HER1-CAR-NK cells after intravenous administration. Consequently, such puerarin@PEGel-assisted HER1-CAR-NK cell treatment exhibits superior tumor suppression efficacy toward both HER1-overexpressing MDA-MB-468 and NCI-H23 human tumor xenografts in mice without inducing obvious side effects. This study highlights a potent strategy to activate CAR-NK cells for augmented treatment of targeted solid tumors through reprogramming tumor immunosuppression.

MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC.

BACKGROUND: The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as "self", evade the surveillance of the immune system, and accumulate to the tumor sites actively. RESULTS: Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate-an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. CONCLUSIONS: These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay.

Abnormal H2O2 levels are closely related to many diseases, including inflammation and cancers. Herein, we simultaneously load HRP and its substrate, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), into liposomal nanoparticles, obtaining a Lipo@HRP&ABTS optical nanoprobe for in vivo H2O2-responsive chromogenic assay with great specificity and sensitivity. In the presence of H2O2, colorless ABTS would be converted by HRP into the oxidized form with strong near-infrared (NIR) absorbance, enabling photoacoustic detection of H2O2 down to submicromolar concentrations. Using Lipo@HRP&ABTS as an H2O2-responsive nanoprobe, we could accurately detect the inflammation processes induced by LPS or bacterial infection in which H2O2 is generated. Meanwhile, upon systemic administration of this nanoprobe we realize in vivo photoacoustic imaging of small s.c. tumors (∼2 mm in size) as well as orthotopic brain gliomas, by detecting H2O2 produced by tumor cells. Interestingly, local injection of Lipo@HRP&ABTS further enables differentiation of metastatic lymph nodes from those nonmetastatic ones, based on their difference in H2O2 contents. Moreover, using the H2O2-dependent strong NIR absorbance of Lipo@HRP&ABTS, tumor-specific photothermal therapy is also achieved. This work thus develops a sensitive H2O2-responsive optical nanoprobe useful not only for in vivo detection of inflammation but also for tumor-specific theranostic applications.

Ultrasound-Responsive Conversion of Microbubbles to Nanoparticles to Enable Background-Free in Vivo Photoacoustic Imaging.

Photoacoustic (PA) imaging based on the photon-to-ultrasound conversion allows the imaging of optical absorbers in deep tissues with high spatial resolution. However, the inherent optical absorbance of biomolecules (e.g., hemoglobin, melanin, etc.) would show up as tissue background signals to interfere with signals from the contrast agent during in vivo PA imaging, limiting the imaging sensitivity. Herein, an ultrasound (US)-responsive PA imaging probe based on microbubbles (MBs) containing gold nanoparticles (Au NPs) is designed for in vivo "background-free" PA imaging. The obtained Au@lip MBs with separated Au NPs decorated within the lipid shell of MBs show low PA signals under near-infrared (NIR) excitation. Interestingly, under exposure to US pulses, those Au@lip MBs would burst to form nanoscale aggregates of Au@lip NPs, which exhibit significantly enhanced NIR PA signals due to their red-shifted surface plasmon resonance. Therefore, by subtracting the PA image captured pre-US burst from that captured post-US burst, the tissue background PA signals could be deducted to enable background-free PA imaging with high sensitivities as demonstrated by multiple ex vivo and in vivo experiments. This work presents a simple yet effective strategy to deduct background signals during PA imaging, which is promising for accurate PA detection of targets in tissues with a strong background.

Amplification of Tumor Oxidative Stresses with Liposomal Fenton Catalyst and Glutathione Inhibitor for Enhanced Cancer Chemotherapy and Radiotherapy.

Amplification of intracellular oxidative stress has been found to be an effective strategy to induce cancer cell death. To this end, we prepare a unique type of ultrasmall gallic acid-ferrous (GA-Fe(II)) nanocomplexes as the catalyst of Fenton reaction to enable persistent conversion of H2O2 to highly cytotoxic hydroxyl radicals (•OH). Then, both GA-Fe(II) and l-buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, are coencapsulated within a stealth liposomal nanocarrier. Interestingly, the obtained BSO/GA-Fe(II)@liposome is able to efficiently amplify intracellular oxidative stress via increasing •OH generation and reducing GSH biosynthesis. After chelating with 99mTc4+ radioisotope, such BSO/GA-Fe(II)@liposome could be tracked under in vivo single-photon-emission-computed-tomography (SPECT) imaging, which illustrates the time-dependent tumor homing of such liposomal nanoparticles after intravenous injection. With GA-Fe(II)-mediated •OH production and BSO-mediated GSH depletion, treatment with such BSO/GA-Fe(II)@liposome would lead to dramatically enhanced intratumoral oxidative stresses, which then result in remarkably improved therapeutic efficacies of concurrently applied chemotherapy or radiotherapy. This work thus presents the concise fabrication of biocompatible BSO/GA-Fe(II)@liposome as an effective adjuvant nanomedicine to promote clinically used conventional cancer chemotherapy and radiotherapy, by greatly amplifying the intratumoral oxidative stress.

Hybrid Protein Nano-Reactors Enable Simultaneous Increments of Tumor Oxygenation and Iodine-131 Delivery for Enhanced Radionuclide Therapy.

It is hard for current radionuclide therapy to render solid tumors desirable therapeutic efficacy owing to insufficient tumor-targeted delivery of radionuclides and severe tumor hypoxia. In this study, a biocompatible hybrid protein nanoreactor composed of human serum albumin (HSA) and catalase (CAT) molecules is constructed via glutaraldehyde-mediated crosslinking. The obtained HSA-CAT nanoreactors (NRs) show retained and well-protected enzyme stability in catalyzing the decomposition of H2 O2 and enable efficient labeling of therapeutic radionuclide iodine-131 (131 I). Then, it is uncovered that such HSA-CAT NRs after being intravenously injected into tumor-bearing mice exhibit efficient passive tumor accumulation as vividly visualized under the fluorescence imaging system and gamma camera. As the result, such HSA-CAT NRs upon tumor accumulation would significantly attenuate tumor hypoxia by decomposing endogenous H2 O2 produced by cancer cells to molecular oxygen, and thereby remarkably improve the therapeutic efficacy of radionuclide 131 I. This study highlights the concise preparation of biocompatible protein nanoreactors with efficient tumor homing and hypoxia attenuation capacities, thus enabling greatly improved tumor radionuclide therapy with promising potential for future clinical translation.

G-Quadruplex-Based Nanoscale Coordination Polymers to Modulate Tumor Hypoxia and Achieve Nuclear-Targeted Drug Delivery for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) is a light-triggered therapy used to kill cancer cells by producing reactive oxygen species (ROS). Herein, a new kind of DNA nanostructure based on the coordination between calcium ions (Ca2+) and AS1411 DNA G quadruplexes to form nanoscale coordination polymers (NCPs) is developed via a simple method. Both chlorine e6 (Ce6), a photosensitizer, and hemin, an iron-containing porphyrin, can be inserted into the G-quadruplex structure in the obtained NCPs. With further polyethylene glycol (PEG) modification, we obtain Ca-AS1411/Ce6/hemin@pHis-PEG (CACH-PEG) NCP nanostructure that enables the intranuclear transport of photosensitizer Ce6 to generate ROS inside cell nuclei that are the most vulnerable to ROS. Meanwhile, the inhibition of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) expression by AS1411 allows for greatly improved PDT-induced cell apoptosis. Furthermore, the catalase-mimicking DNAzyme function of G-quadruplexes and hemin in those NCPs could decompose tumor endogenous H2O2 to in situ generate oxygen so as to further enhance PDT by overcoming the hypoxia-associated resistance. This work develops a simple yet general method with which to fabricate DNA-based NCPs and presents an interesting concept of a nanoscale drug-delivery system that could achieve the intranuclear delivery of photosensitizers, the down-regulation of anti-apoptotic proteins, and the modulation of the unfavorable tumor microenvironment simultaneously for improved cancer therapy.

Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer.

Photodynamic therapy (PDT) is an oxygen-dependent light-triggered noninvasive therapeutic method showing many promising aspects in cancer treatment. For effective PDT, nanoscale carriers are often needed to realize tumor-targeted delivery of photosensitizers, which ideally should further target specific cell organelles that are most vulnerable to reactive oxygen species (ROS). Second, as oxygen is critical for PDT-induced cancer destruction, overcoming hypoxia existing in the majority of solid tumors is important for optimizing PDT efficacy. Furthermore, as PDT is a localized treatment method, achieving systemic antitumor therapeutic outcomes with PDT would have tremendous clinical values. Aiming at addressing the above challenges, we design a unique type of enzyme-encapsulated, photosensitizer-loaded hollow silica nanoparticles with rationally designed surface engineering as smart nanoreactors. Such nanoparticles with pH responsive surface coating show enhanced retention responding to the acidic tumor microenvironment and are able to further target mitochondria, the cellular organelle most sensitive to ROS. Meanwhile, decomposition of tumor endogenous H2O2 triggered by those nanoreactors would lead to greatly relieved tumor hypoxia, further favoring in vivo PDT. Moreover, by combining our nanoparticle-based PDT with check-point-blockade therapy, systemic antitumor immune responses could be achieved to kill nonirradiated tumors 1-2 cm away, promising for metastasis inhibition.

Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.

Surfactant-Stripped Micelles of Near Infrared Dye and Paclitaxel for Photoacoustic Imaging Guided Photothermal-Chemotherapy.

Development of nanoagents with strong near-infrared (NIR) absorbance and high photothermal conversion capacity is highly desired for efficient photoacoustic (PA) imaging and photothermal therapy of cancers. Herein, surfactant-stripped micelles with photostable near-infrared dye, ß-thiophene-fused BF2 -azadipyrromethene (aza-BDTP), are prepared in the presence of paclitaxel (PTX) with Pluronic F127 as the surfactant. Distinct from hydrophobic aza-BDTP and PTX, the obtained surfactant-stripped micelles aza-BDTP/PTX show excellent solubility, physiological stability, and high loading efficiencies for corresponding aza-BDTP and PTX. Intriguingly, these aza-BDTP/PTX micelles exhibit high photothermal conversion efficiency at 33.9%, significantly higher than 16.9% for bare aza-BDTP molecules, owing to aggregation-induced quenching of aza-BDTP fluorescence. With excellent photostability, aza-BDTP/PTX micelles appear to be a highly stable photoacoustic imaging probe and show efficient tumor accumulation as visualized under photoacoustic imaging upon intravenous injection. After being irradiated with a 785 nm laser, 4T1 tumors on the mice with systemic administration of aza-BDTP/PTX micelles are fully eradiated without any recurrences within 60 d. This work presents a general method for efficient encapsulation of hydrophobic aza-BDTP and PTX, obtaining hybrid aza-BDTP/PTX micelles as promising nanotheranostics for imaging guided cancer combination therapy.

Renal-Clearable PEGylated Porphyrin Nanoparticles for Image-guided Photodynamic Cancer Therapy.

Noninvasive dynamic positron emission tomography (PET) imaging was used to investigate the balance between renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)-modified porphyrin nanoparticles (TCPP-PEG) with various molecular weights. TCPP-PEG10K nanoparticles with clearance behavior would be a good candidate for PET image-guided photodynamic therapy.

Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies.

Tumor hypoxia is known to be one of critical reasons that limit the efficacy of cancer therapies, particularly photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is needed in the process of cancer cell destruction. Herein, taking advantages of the great biocompatibility and high oxygen dissolving ability of perfluorocarbon (PFC), we develop an innovative strategy to modulate the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle for ultrasound triggered tumor-specific delivery of oxygen. In our experiment, nanodroplets of PFC stabilized by albumin are intravenously injected into tumor-bearing mice under hyperoxic breathing. With a low-power clinically adapted ultrasound transducer applied on their tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly release oxygen in the tumor under ultrasound stimulation, and then circulate back into the lung for reoxygenation. Such repeated cycles would result in dramatically enhanced tumor oxygenation and thus remarkably improved therapeutic outcomes in both PDT and RT treatment of tumors. Importantly, our strategy may be applied for different types of tumor models. Hence, this work presents a simple strategy to promote tumor oxygenation with great efficiency using agents and instruments readily available in the clinic, so as to overcome the hypoxia-associated resistance in cancer treatment.

Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy.

Photodynamic therapy (PDT) is considered as a safe and selective way to treat a wide range of cancers as well as nononcological disorders. However, as oxygen is required in the process of PDT, the hypoxic tumor microenvironment has largely limited the efficacy of PDT to treat tumors especially those with relatively large sizes. To this end, we uncover that hyaluronidase (HAase), which breaks down hyaluronan, a major component of extracellular matrix (ECM) in tumors, would be able to enhance the efficacy of nanoparticle-based PDT for in vivo cancer treatment. It is found that the administration of HAase would lead to the increase of tumor vessel densities and effective vascular areas, resulting in increased perfusion inside the tumor. As a result, the tumor uptake of nanomicelles covalently linked with chlorine e6 (NM-Ce6) would be increased by ∼2 folds due to the improved "enhanced permeability and retention" (EPR) effect, while the tumor oxygenation level also shows a remarkable increase, effectively relieving the hypoxia state inside the tumor. Those effects taken together offer significant benefits in greatly improving the efficacy of PDT delivered by nanoparticles. Taking advantage of the effective migration of HAase from the primary tumor to its drainage sentinel lymph nodes (SLNs), we further demonstrate that this strategy would be helpful to the treatment of metastatic lymph nodes by nanoparticle-based PDT. Lastly, both enhanced EPR effect of NM-Ce6 and relieved hypoxia state of tumor are also observed after systemic injection of modified HAase, proving its potential for clinical translation. Therefore, our work presents a new concept to improve the efficacy of nanomedicine by modulating the tumor microenvironment.

Surface coating-dependent cytotoxicity and degradation of graphene derivatives: towards the design of non-toxic, degradable nano-graphene.

With the increasing interests of using graphene and its derivatives in the area of biomedicine, the systematic evaluation of their potential risks and impacts to biological systems is becoming critically important. In this work, we carefully study how surface coatings affect the cytotoxicity and extracellular biodegradation behaviors of graphene oxide (GO) and its derivatives. Although naked GO could induce significant toxicity to macrophages, coating those two-dimensional nanomaterials with biocompatible macromolecules such as polyethylene glycol (PEG) or bovine serum albumin (BSA) could greatly attenuate their toxicity, as independently evidenced by several different assay approaches. On the other hand, although GO can be gradually degraded through enzyme induced oxidization by horseradish peroxidase (HRP), both PEG and BSA coated GO or reduced GO (RGO) are rather resistant to HRP-induced biodegradation. In order to obtain biocompatible functionalized GO that can still undergo enzymatic degradation, we conjugate PEG to GO via a cleavable disulfide bond, obtaining GO-SS-PEG with negligible toxicity and considerable degradability, promising for further biomedical applications.

Supramolecular self-assembly enhanced europium(III) luminescence under visible light.

In this paper, we report on the luminescence of europium by directly exciting europium ions with visible light in aqueous medium. Upon replacing all the water molecules that coordinate around a central europium ion with a ditopic ligand 1,11-bis(2,6-dicarboxypyridin-4-yloxy)-3,6,9-trioxaundecane (L2EO4), the quenching from water molecules is efficiently eliminated, offering considerable europium emission. By stoichiometrically mixing with a positively charged block polyelectrolyte, the negatively charged L2EO4-Eu coordinating complex can be transformed into a coordination 'polymer', which simultaneously forms electrostatic micelles with further enhanced europium fluorescence emission, owing to the increased fraction of L2EO4-coordinated Eu(III) as revealed by the fluorescence lifetime measurements. This approach avoids the use of the antenna effect that often utilizes UV light as the irradiation source. We further use those micelles for bio-imaging, and for the first time demonstrate the use of directly excited Eu-containing nano-probes for in vivo fluorescence imaging in small animals under visible excitation. Although literature results have shown that the direct excitation of europium ions in water may lead to emissions in the presence of coordinating ligands, those emissions were too weak to be applied due to the remaining water molecules in the coordination sphere. Our work points out that the direct excitation of europium can generate considerable europium emission given that all the water molecules in the coordination sphere are excluded, which does not only greatly reduce tedious lab work in synthesizing antenna molecules, but also facilitates the application of europium in aqueous medium under visible light.

Nano-graphene in biomedicine: theranostic applications.

Owing to their unique physical and chemical properties, graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (RGO) and GO-nanocomposites have attracted tremendous interest in many different fields including biomedicine in recent years. With every atom exposed on its surface, single-layered graphene shows ultra-high surface area available for efficient molecular loading and bioconjugation, and has been widely explored as novel nano-carriers for drug and gene delivery. Utilizing the intrinsic near-infrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been realized, achieving excellent anti-tumor therapeutic efficacy in animal experiments. A variety of inorganic nanoparticles can be grown on the surface of nano-graphene, obtaining functional graphene-based nanocomposites with interesting optical and magnetic properties useful for multi-modal imaging and imaging-guided cancer therapy. Moreover, significant efforts have also been devoted to study the behaviors and toxicology of functionalized nano-graphene in animals. It has been uncovered that both surface chemistry and sizes play key roles in controlling the biodistribution, excretion, and toxicity of nano-graphene. Biocompatibly coated nano-graphene with ultra-small sizes can be cleared out from body after systemic administration, without rendering noticeable toxicity to the treated mice. In this review article, we will summarize the latest progress in this rapidly growing field, and discuss future prospects and challenges of using graphene-based materials for theranostic applications.

Tumor Microenvironment Modulating CaCO3 -Based Colloidosomal Microreactors Can Generally Reinforce Cancer Immunotherapy.

Tumor hypoxia and acidity, two general features of solid tumors, are known to have negative effect on cancer immunotherapy by directly causing dysfunction of effector immune cells and promoting suppressive immune cells inside tumors. Herein, a multifunctional colloidosomal microreactor is constructed by encapsulating catalase within calcium carbonate (CaCO3 ) nanoparticle-assembled colloidosomes (abbreviated as CaP CSs) via the classic double emulsion method. The yielded CCaP CSs exhibit well-retained proton-scavenging and hydrogen peroxide decomposition performances and can thus neutralize tumor acidity, attenuate tumor hypoxia, and suppress lactate production upon intratumoral administration. Consequently, CCaP CSs treatment can activate potent antitumor immunity and thus significantly enhance the therapeutic potency of coloaded anti-programmed death-1 (anti-PD-1) antibodies in both murine subcutaneous CT26 and orthotopic 4T1 tumor xenografts. In addition, such CCaP CSs treatment also markedly reinforces the therapeutic potency of epidermal growth factor receptor expressing chimeric antigen receptor T (EGFR-CAR-T) cells toward a human triple-negative breast cancer xenograft by promoting their tumor infiltration and effector cytokine secretion. Therefore, this study highlights that chemical modulation of tumor acidity and hypoxia can collectively reverse tumor immunosuppression and thus significantly potentiate both immune checkpoint blockade and CAR-T cell immunotherapies toward solid tumors.

Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X-C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X-C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME.

Self-fueling ferroptosis-inducing microreactors based on pH-responsive Lipiodol Pickering emulsions enable transarterial ferro-embolization therapy.

Lipiodol chemotherapeutic emulsions remain one of the main choices for the treatment of unresectable hepatocellular carcinoma (HCC) via transarterial chemoembolization (TACE). However, the limited stability of Lipiodol chemotherapeutic emulsions would lead to rapid drug diffusion, which would reduce the therapeutic benefit and cause systemic toxicity of administrated chemotherapeutics. Therefore, the development of enhanced Lipiodol-based formulations is of great significance to enable effective and safe TACE treatment. Herein, a stable water-in-oil Lipiodol Pickering emulsion (LPE) stabilized by pH-dissociable calcium carbonate nanoparticles and hemin is prepared and utilized for efficient encapsulation of lipoxygenase (LOX). The obtained LOX-loaded CaCO3&hemin-stabilized LPE (LHCa-LPE) showing greatly improved emulsion stability could work as a pH-responsive and self-fueling microreactor to convert polyunsaturated fatty acids (PUFAs), a main component of Lipiodol, to cytotoxic lipid radicals through the cascading catalytic reaction driven by LOX and hemin, thus inducing ferroptosis of cancer cells. As a result, such LHCa-LPE upon transcatheter embolization can effectively suppress the progression of orthotopic N1S1 HCC in rats. This study highlights a concise strategy to prepare pH-responsive and stable LPE-based self-fueling microreactors, which could serve as bifunctional embolic and ferroptosis-inducing agents to enable proof-of-concept transarterial ferro-embolization therapy of HCC.