An Intelligent DNA Nanoreactor for Easy-to-Read In Vivo Tumor Imaging and Precise Therapy.

Nanomaterial-based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent "always ON" or single-parameter responsive signal output, substantial off-target effects, and high cost. Therefore, achieving in vivo easy-to-read tumor imaging and precise therapy in a multi-parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the "AND" Boolean logic algorithm to address these issues. iDNR-mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers "AND" hydrogen peroxide (H2 O2 ). Therefore, intelligent temperature-based in vivo easy-to-read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.

DNA Engineered Lymphocyte-Based Homologous Targeting Artificial Antigen-Presenting Cells for Personalized Cancer Immunotherapy.

Artificial antigen-presenting cells (aAPCs) constructed by integrating T cell activation ligands on biocompatible materials hold great potential in tumor immunotherapy. However, it remains challenging to develop aAPCs, which could mimic the characteristics of natural APCs, thereby realizing antigen-specific T cells activation in vivo. Here, we report the first effort to construct natural lymphocyte-based homologous targeting aAPCs (LC-aAPCs) with lipid-DNA-mediated noninvasive live cell surface engineering. Through a predesigned bottom-up self-assembly path, we achieved natural-APC-mimicking distribution of T cell activation ligands on LC-aAPCs, which would enable the optimized T cell activation. Moreover, the lipid-DNA-mediated self-assembly occurring on lipid bilayers would not affect the functions of homing receptors expressed on lymphocyte. Therefore, such LC-aAPCs could actively migrate to peripheral lymphatic organs and then effectively activate antigen-specific T cells. Combined with an immune checkpoint inhibitor, such LC-aAPCs could effectively inhibit the growth of different tumor models. Thus, our work provides a new design of aAPCs for in vivo applications in tumor immunotherapy, and the lipid-DNA-mediated noninvasive live cell surface engineering would be a powerful tool for designing cell-based therapeutics.

High-Yield, Magnetic Harvesting of Extracellular Outer-Membrane Vesicles from Escherichia coli.

Extracellular outer-membrane vesicles (OMVs) are attractive for use as drug nanocarriers, because of their high biocompatibility and ability to enter cells. However, widespread use is hampered by low yields. Here, a high-yield method for magnetic harvesting of OMVs from Escherichia coli is described. To this end, E. coli are grown in the presence of magnetic iron-oxide nanoparticles (MNPs). Uptake of MNPs by E. coli is low and does not increase secretion of OMVs. Uptake of MNPs can be enhanced through PEGylation of MNPs. E. coli growth in the presence of PEGylated MNPs increases bacterial MNP-uptake and OMV-secretion, accompanied by upregulation of genes involved in OMV-secretion. OMVs containing MNPs can be magnetically harvested at 60-fold higher yields than achieved by ultracentrifugation. Functionally, magnetically-harvested OMVs and OMVs harvested by ultracentrifugation are both taken-up in similar numbers by bacteria. Uniquely, in an applied magnetic field, magnetically-harvested OMVs with MNPs accumulate over the entire depth of an infectious biofilm. OMVs harvested by ultracentrifugation without MNPs only accumulate near the biofilm surface. In conclusion, PEGylation of MNPs is essential for their uptake in E. coli and yields magnetic OMVs allowing high-yield magnetic-harvesting. Moreover, magnetic OMVs can be magnetically targeted to a cargo delivery site in the human body.

Equipping Cancer Cell Membrane Vesicles with Functional DNA as a Targeted Vaccine for Cancer Immunotherapy.

By inducing tumor-specific immune responses, tumor vaccines have recently aroused great research interest. Herein, we design a targeted nanovaccine by equipping cell membrane vesicles (CMVs) harvested from tumor cells with functional DNA including CpG oligonucleotide, an agonist for toll-like receptor 9, as well as an aptamer targeting the dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) receptor overexpressed on DCs. Such DNA-modified CMVs could target DCs and further stimulate their maturation. Notably, our nanovaccines could trigger robust antitumor immune responses to effective delay the tumor growth. Moreover, the combination of CMV-based nanovaccines with an immune checkpoint blockade could result in improved therapeutic responses by eliminating the majority of the tumors as well as long-term immune memory to prevent tumor recurrence. Therefore, by simply assembling functional DNA on CMVs harvested from tumor cells, we propose a general platform of DC-targeted personalized cancer vaccines for effective and specific cancer immunotherapy.

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.

Injectable Anti-inflammatory Nanofiber Hydrogel to Achieve Systemic Immunotherapy Post Local Administration.

Despite the great promise achieved by immune checkpoint blockade (ICB) therapy in harnessing the immune system to combat different tumors, limitations such as low objective response rates and adverse effects remain to be resolved. Here, an anti-inflammatory nanofiber hydrogel self-assembled by steroid drugs is developed for local delivery of antiprogrammed cell death protein ligand 1 (αPDL1). Interestingly, on the one hand this carrier-free system based on steroid drugs can reprogram the pro-tumoral immunosuppressive tumor microenvironment (TME) to antitumoral TME; on the other hand, it would serve as a reservoir for sustained release of αPDL1 so as to synergistically boost the immune system. By local injection of such αPDL1-loaded hydrogel, effective therapeutic effects were observed in inhibiting both local tumors and abscopal tumors without any treatment. This work presents a unique hydrogel-based delivery system using clinically approved drugs, showing promise in improving the objective response rate of ICB therapy and minimizing its systemic toxicity.

Ultrafine Titanium Monoxide (TiO1+x) Nanorods for Enhanced Sonodynamic Therapy.

Ultrasound (US)-triggered sonodynamic therapy (SDT) that enables noninvasive treatment of large internal tumors has attracted widespread interest. For improvement in the therapeutic responses to SDT, more effective and stable sonosensitizers are still required. Herein, ultrafine titanium monoxide nanorods (TiO1+x NRs) with greatly improved sono-sensitization and Fenton-like catalytic activity were fabricated and used for enhanced SDT. TiO1+x NRs with an ultrafine rodlike structure were successfully prepared and then modified with polyethylene glycol (PEG). Compared to the conventional sonosensitizer, TiO2 nanoparticles, the PEG-TiO1+x NRs resulted in much more efficient US-induced generation of reactive oxygen species (ROS) because of the oxygen-deficient structure of TiO1+x NR, which predominantly serves as the charge trap to limit the recombination of US-triggered electron-hole pairs. Interestingly, PEG-TiO1+x NRs also exhibit horseradish-peroxidase-like nanozyme activity and can produce hydroxyl radicals (•OH) from endogenous H2O2 in the tumor to enable chemodynamic therapy (CDT). Because of their efficient passive retention in tumors post intravenous injection, PEG-TiO1+x NRs can be used as a sonosensitizer and CDT agent for highly effective tumor ablation under US treatment. In addition, no significant long-term toxicity of PEG-TiO1+x NRs was found for the treated mice. This work highlights a new type of titanium-based nanostructure with great performance for tumor SDT.

Iron Nanoparticles for Low-Power Local Magnetic Hyperthermia in Combination with Immune Checkpoint Blockade for Systemic Antitumor Therapy.

Magnetic hyperthermia (MHT) utilizing heat generated by magnetic nanoparticles under alternating magnetic field (AMF) is an effective local tumor ablation method but can hardly treat metastatic tumors. In this work, we discover that pure iron nanoparticles (FeNPs) with high magnetic saturation intensity after being modified by biocompatible polymers are stable in aqueous solution and could be employed as a supereffective MHT agent to generate sufficient heating under a low-power AFM. Effective MHT ablation of tumors is then achieved, using either locally injected FeNPs or intravenously injected FeNPs with the help of locally applied tumor-focused constant magnetic field to enhance the tumor accumulation of those nanoparticles. We further demonstrate that the combination of FeNP-based MHT with local injection of nanoadjuvant and systemic injection of anticytotoxic T-lymphocyte antigen-4 (anti-CTLA4) checkpoint blockade would result in systemic therapeutic responses to inhibit tumor metastasis. A robust immune memory effect to prevent tumor recurrence is also observed after the combined MHT-immunotherapy. This work not only highlights that FeNPs with appropriate surface modification could act as a supereffective MHT agent but also presents the great promises of combining MHT with immunotherapy to achieve long-lasting systemic therapeutic outcome after local treatment.

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.

NaCeF4:Gd,Tb Scintillator as an X-ray Responsive Photosensitizer for Multimodal Imaging-Guided Synchronous Radio/Radiodynamic Therapy.

Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.

[Analysis of classical prescription Jinshui Liujun Jian based on ancient literature].

To provide the ancient literary evidence support for the clinical application and development of classical prescription based on systematical collection and analysis of the ancient Chinese medical literature containing Jinshui Liujun Jian, including its origin and development. Bibliometric analysis was used and information of Jinshui Liujun Jian in ancient Chinese medical literature was then collected for statistical analysis of formula compositions, main indications, dosage, preparation methods, etc. A total of 151 valid items of data were obtained from 48 ancient Chinese medicine books. Jinshui Liujun Jian was first recorded in Jingyue Quanshu written by ZHANG Jiebin. This prescription consisted of Rehmanniae Radix Praeparata, Angelicae Sinensis Radix, Pinelliae Rhizome, Citri Reticulatae Pericarpium, Poria and Glycyrrhizae Radix et Rhizome Praeparata cum Melle, and it was mainly used to treat the deficiency of lung and kidney, edema and excess production of phlegm, or Yin deficiency in the old, insufficient blood-qi, wind-cold evil, cough and disgusting, asthma and excessive phlegm. Doctors in later dynasties mostly followed the prescription compositions, dosages and indications in Jingyue Quanshu, and extended the clinical application of this prescription.

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.

Tumor-pH-Responsive Dissociable Albumin-Tamoxifen Nanocomplexes Enabling Efficient Tumor Penetration and Hypoxia Relief for Enhanced Cancer Photodynamic Therapy.

Despite the promises of applying nano-photosensitizers (nano-PSs) for photodynamic therapy (PDT) against cancer, severe tumor hypoxia and limited tumor penetration of nano-PSs would lead to nonoptimized therapeutic outcomes of PDT. Therefore, herein a biocompatible nano-PS is prepared by using tamoxifen (TAM), an anti-estrogen compound, to induce self-assembly of chlorin e6 (Ce6) modified human serum albumin (HSA). The formed HSA-Ce6/TAM nanocomplexes, which are stable under neutral pH with a diameter of ≈130 nm, would be dissociated into individual HSA-Ce6 and TAM molecules under the acidic tumor microenvironment, owing to the pH responsive transition of TAM from hydrophobic to hydrophilic. Upon systemic administration, such HSA-Ce6/TAM nanoparticles exhibit prolonged blood circulation and high accumulation in the tumor, where it would undergo rapid pH responsive dissociation to enable obviously enhanced intratumoral penetration of HSA-Ce6. Furthermore, utilizing the ability of TAM in reducing the oxygen consumption of cancer cells, it is found that HSA-Ce6/TAM after systemic administration could efficiently attenuate the tumor hypoxia status. Those effects acting together lead to remarkably enhanced PDT treatment. This work presents a rather simple approach to fabricate smart nano-PSs with multiple functions integrated into a single system via self-assembly of all-biocompatible components, promising for the next generation cancer PDT.

Drug-Loaded Mesoporous Tantalum Oxide Nanoparticles for Enhanced Synergetic Chemoradiotherapy with Reduced Systemic Toxicity.

Combining chemotherapy and radiotherapy (chemoradiotherapy) has been widely applied in many clinical practices, showing promises in enhancing therapeutic outcomes. Nontoxic nanocarriers that not only are able to deliver chemotherapeutics into tumors, but could also act as radiosensitizers to enhance radiotherapy would thus be of great interest in the development of chemoradiotherapies. To achieve this aim, herein mesoporous tantalum oxide (mTa2 O5 ) nanoparticles with polyethylene glycol (PEG) modification are fabricated. Those mTa2 O5 -PEG nanoparticles could serve as a drug delivery vehicle to allow efficient loading of chemotherapeutics such as doxorubicin (DOX), whose release appears to be pH responsive. Meanwhile, owing to the interaction of Ta with X-ray, mTa2 O5 -PEG nanoparticles could offer an intrinsic radiosensitization effect to increase X-ray-induced DNA damages during radiotherapy. As a result, DOX-loaded mTa2 O5 -PEG (mTa2 O5 -PEG/DOX) nanoparticles can offer a strong synergistic therapeutic effect during the combined chemoradiotherapy. Furthermore, in chemoradiotherapy, such mTa2 O5 -PEG/DOX shows remarkably reduced side effects compared to free DOX, which at the same dose appears to be lethal to animals. This work thus presents a new type of mesoporous nanocarrier particularly useful for the delivery of safe and effective chemoradiotherapy.

Degradable Vanadium Disulfide Nanostructures with Unique Optical and Magnetic Functions for Cancer Theranostics.

Multifunctional biodegradable inorganic theranostic nano-agents are of great interest to the field of nanomedicine. Upon lipid modification, VS2 nanosheets could be converted into ultra-small VS2 nanodots encapsulated inside polyethylene glycol (PEG) modified lipid micelles. Owing to paramagnetism, high near-infrared (NIR) absorbance, and chelator-free 99m Tc4+ labeling of VS2 , such VS2 @lipid-PEG nanoparticles could be used for T1-weighted magnetic resonance (MR), photoacoustic (PA),and single photon emission computed tomography (SPECT) tri-modal imaging guided photothermal ablation of tumors. Importantly, along with the gradual degradation of VS2 , our VS2 @lipid-PEG nanoparticles exhibit effective body excretion without appreciable toxicity. The unique advantages of VS2 nanostructures with highly integrated functionalities and biodegradable behaviors mean they are promising for applications in cancer theranostics.

Biomineralization-inspired synthesis of autologous cancer vaccines for personalized metallo-immunotherapy.

Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn2+, the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8+ T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.

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.

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.