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Radiation therapy (RT) is one of the most widely used cancer treatments. However, the vigorous biosynthesis of cancer cells plays an important role for RT resistance. Herein, we develop a hafnium-based nanoscale metal-organic frameworks (Hf-nMOFs) loaded with 3-bromopyruvate (3-BrPA) to overcome RT resistance and achieve favorable RT efficacy. The deposition of X-rays is greatly enhanced by Hf-nMOFs to induce stronger damage to DNA in RT. Simultaneously, as an inhibitor of glycolysis, the loaded 3-BrPA can reduce the supply of energy and interfere with the biosynthesis of proteins to decrease the DNA damage repair. As a result, the 3-BrPA@Hf-nMOFs (BHT) will overcome the RT resistance and enhance the curative effect of RT. Up and down-regulated genes as well as the related pathways in cellular metabolism and biosynthesis are well investigated to reveal the radiosensitization mechanism of BHT. In addition, the Hf element endows BHT with CT imaging capability to real-timely monitor the therapeutic process. Hence, the designed strategy of biosynthesis-targeted radiosensitization could decrease the doses of ionizing radiations and provide fresh perspectives on cancer treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In clinics, therapeutic proteins are commonly used to treat retinal diseases through intraocular injection, the treatment which suffers from rather low patient compliance. Topical administration (e.g. eye-drops) of large molecule drugs remains a major challenge due to the presence of various barriers in the eye. In this study, zwitterion-grafted chitosan (CS-ZW) was developed and then self-assembled with protein therapeutics including adalimumab (ADA) or catalase (CAT) for the treatment of dry age-related macular degeneration (dAMD) via topical eyedrops. Since CS-ZW can cross the mucus layer and open the tight junctions between epithelial cells, their delivered therapeutic proteins can be shuttled across the ocular barriers to reach the diseased site in the fundus. CS-ZW/ADA eyedrops delivering ADA to bind TNF-α in the fundus achieved a similar therapeutic effect to intravitreal ADA injection in a mouse dAMD model. In addition, the therapeutic effect was further improved by combining eyedrop formulations of CS-ZW/ADA and CS-ZW/CAT, the latter of which can clear reactive oxygen species (ROS) in the lesion to further assist dAMD treatment. Our work provides a simple and effective delivery vehicle that can non-invasively treat fundus diseases such as dAMD, showing potential advantages in reducing side effects associated with intraocular injection and improving patient compliance. [ABSTRACT FROM AUTHOR]

Treatment of acute bacterial meningitis is difficult due to the impermeability of the blood-brain barrier, greatly limiting the antibiotic concentrations that can be achieved in the brain. Escherichia coli grown in presence of iron-oxide magnetic nanoparticles secrete large amounts of magnetic outer-membrane vesicles (OMVs) in order to remove excess Fe from their cytoplasm. OMVs are fully biomimetic nanocarriers, but can be inflammatory. Here, non-inflammatory magnetic OMVs were prepared from an E. coli strain in which the synthesis of inflammatory lipid A acyltransferase was inhibited using CRISPR/Cas9 mediated gene knockout. OMVs were loaded with ceftriaxone (CRO) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) and magnetically driven across the blood-brain barrier for sonodynamic treatment of bacterial meningitis. ROS-generation upon ultrasound application of CRO- and TCPP-loaded OMVs yielded similar ROS-generation as by TCPP in solution. In vitro , ROS-generation by CRO- and TCPP-loaded OMVs upon ultrasound application operated synergistically with CRO to kill a hard-to-kill, CRO-tolerant E. coli strain. In a mouse model of CRO-tolerant E. coli meningitis, CRO- and TCPP-loaded OMVs improved survival rates and clinical behavioral scores of infected mice after magnetic targeting and ultrasound application. Recurrence did not occur for at least two weeks after arresting treatment. [Display omitted] • Magnetically-harvested OMVs can be magnetically driven across the blood-brain barrier • Magnetic OMVs can be loaded with an antibiotic and a sonosensitizer • Antibiotics work synergistically in bacterial killing with sonodynamically generated ROS • Magnetic OMVs loaded with CRO and TCPP effectively cures murine, bacterial meningitis • Treatment with CRO-TCPP loaded OMVs delays recurrence of murine, bacterial meningitis [ABSTRACT FROM AUTHOR]

A variety of bioactive materials are currently developed to expand T cells ex vivo for adoptive T cell immunotherapy, also known as called artificial antigen-presenting cells (aAPCs). However, almost all the reported designs exhibit relatively smooth surface modified with T cell activating biomolecules, and therefore cannot well mimic the dendritic morphological characteristics of dendritic cells (DCs), the most important type of natural antigen-presenting cells (APCs) with high specific surface areas. Here, we propose a hydrophilic monomer-mediated surface morphology control strategy to synthesize biocompatible dendritic poly(N-isopropylacrylamide) (PNIPAM) microspheres for constructing aAPCs with surface morphology mimicking natural APCs (e.g., DCs). Interestingly, when maintaining the same ligands density, dendritic polymeric microspheres-based aAPCs (DPM beads) can more efficiently expand CD8+ T cells than that with smooth surfaces. Moreover, adoptive transfer of antigen-specific CD8+ T cells expanded by the DPM beads show significant antitumor effect of B16-OVA tumor bearing mice. Therefore, we provide a new concept for constructing biomimetic aAPCs with enhanced T cell expansion ability. [Display omitted] [ABSTRACT FROM AUTHOR]

Physiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Herein, we discovered that metformin, a prescribed drug for type 2 diabetes, could up-regulate the oxidative phosphorylation of CAR-T cells, increase their energy metabolism, and further promote their proliferation. Inspired by this finding, we designed a hydrogel scaffold to co-deliver metformin and CAR-T cells by adding CAR-T cells into a lyophilized alginate hydrogel containing metformin. The obtained hydrogel scaffold after being implanted into the tumor resection cavity could act as a cell reservoir to sustainably release both CAR-T cells and metformin. While the released metformin could suppress oxidative and glycolytic metabolism of cancer cells and lead to decreased tumor hypoxia, CAR-T cells would respond to metformin by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype, contributing to elevated antitumor responses. As demonstrated in several post-surgical tumor models, the proliferation and tumor-infiltration of CAR-T cells were significantly enhanced and the treatment efficacy of CAR-T cells was augmented, against both local tumors and distant abscopal tumors, while showing reduced systemic immune-related adverse effects. Our work presents a new strategy to achieve effective yet safe CAR-T therapy against solid tumors using a cell-delivery scaffold based on clinically validated drugs and biomaterials. [ABSTRACT FROM AUTHOR]

Oxidative stress and mitochondrial damage are the main mechanisms of ischemia-reperfusion injury in ischemic stroke. Herein, cerium oxide nanoparticles with powerful free radical scavenging ability were used as carriers to load dl-3- n -butylphthalide (NBP–CeO 2 NPs) for the combined treatment of ischemic stroke. NBP-CeO 2 NPs could eliminate reactive oxygen species (ROS) in mouse brain microvascular endothelial cells and hippocampal neurons after oxygen-glucose deprivation/reoxygenation (OGD/R), and also save mitochondrial membrane potential, morphology, and function, thus alleviating the in vitro blood brain barrier (BBB) disruption and neuronal apoptosis. In the middle cerebral artery embolization/recanalization (MCAO/R) mouse model, the NBP-CeO 2 NPs also possessed superior ROS scavenging ability, protected mitochondria, and preserved BBB integrity, thereby reducing cerebral infarction and cerebral edema and inhibiting neuroinflammation and neuronal apoptosis. The long-term neurobehavioral tests indicated that the NBP-CeO 2 NPs significantly improved sensorimotor function and spatial learning ability by promoting angiogenesis after ischemic stroke. Therefore, the NBP-CeO 2 NPs provided a novel therapeutic approach for ischemic stroke by combining antioxidant and neurovascular repair abilities, highlighting its wide application in ischemia-reperfusion injury. [Display omitted] [ABSTRACT FROM AUTHOR]

Considering the huge cost and long test periods required for new drug development, repurposing drugs that have already been applied in the clinic as new cancer treatment candidates represents an attractive alternative. Disulfiram (DSF) was originally used to treat alcoholism and has proven to have anticancer effects with the coadministration of copper ions (Cu2+). However, the limited water-solubility of DSF and systemic toxicity induced by exogenous Cu2+ hinder its practical application. Herein, we constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu2+ and DSF. After intravenous injection, those nanoparticles with long blood half-life preferentially accumulate in tumors, followed by the degradation of nanoparticles in response to the acidic tumor microenvironment, subsequently releasing Cu2+ and DSF to generate cytotoxic metabolite DTC−Copper complex, bis(diethyldithiocarbamate)–copper (CuET) for tumor treatment. In addition to direct cytotoxicity, the active metabolite CuET could effectively induce immunogenic cell death (ICD) of cancer cells to regulate the immunosuppressive tumor microenvironment, contributing to enhanced immune checkpoint blockade (ICB) therapy in triggering systemic immune responses. This work thus demonstrates the great promises of repurposing the old drug DSF as a new ICD inducer with nano-formulation, to achieve improved synergetic tumor-responsive therapy with low side effects. [ABSTRACT FROM AUTHOR]

Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors. [ABSTRACT FROM AUTHOR]

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is emerging as a non-invasive strategy to eradicate tumors, but its therapeutic efficacy is still not ideal. To achieve more effective SDT, water insoluble sonosensitizer meso-5, 10, 15, 20-tetra(4-hydroxylphenyl)porphyrin (THPP) is here esterified with succinic acid conjugated oxaliplatin prodrug (Oxa(IV)SA 2) and carboxyl group terminated PEG (PEG 5k -COOH). The obtained covalent organic polymer (COP) of THPP-Oxa(IV)-PEG with good physiological stability, sonosensitization efficacy and glutathione (GSH) responsive oxalipatin responsive behaviors can induce effective immunogenic cancer cell death upon the ultrasound exposure. In addition, THPP-Oxa(IV)-PEG is shown to be a versatile carrier for both hydrophobic near infrared dye and radioisotope 99mTc, thereby enabling real-time tracking of its pharmacokinetics behavior under corresponding imaging facilities. Furthermore, treatment with THPP-Oxa(IV)-PEG injection and ultrasound exposure is shown to be most effectively in suppressing tumor growth, with 3 of 6 CT26 tumor bearing mice fully cured, ascribing to its high potency in eliciting profound antitumor immune responses. This work highlights a promising strategy in constructing multifunctional nanosonosensitizer as a potent immunogenic nanomedicine to enhance the treatment outcome of SDT. [ABSTRACT FROM AUTHOR]

Intravesical instillation of chemotherapeutics or immune-stimulating agents could reduce the recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumors. Its efficacy, however, remains to be improved due to the bladder epithelial barrier. Although certain transmucosal delivery carriers are able to enhance the transepithelial penetration of intravesical agents, they could hardly differentiate carcinoma and adjacent normal tissues of the bladder wall. Here, we reported polyethylene glycol (PEG) & glutaraldehyde co-modified fluorinated chitosan (PGFCS) as a collagen-targeted transepithelial penetration enhancer, which could create a tumor-targeted adhesive interface by the aldehyde-selective reaction with collagen amines enriched in the tumor, thus opening the transepithelial-delivery barrier at the tumor site though the fluorinated-chitosan-mediated tight junction regulation. Interestingly, with the help of PGFCS pre-treatment, intravesical instillation of chemotherapeutics pirabucin (THP) combined with immune stimulating agent interleukin-12 could trigger potent antitumor chemoimmunotherapeutic responses in destructing orthotopic bladder tumors and inhibiting cancer recurrence. Our work presents a unique type of tumor-specific transepithelial penetration enhancer, which shows great potential for safe and effective intravesical instillation of NMIBC. [Display omitted] [ABSTRACT FROM AUTHOR]

The limited penetration depth of external excitation light would remarkably impair the therapeutic efficacy of photodynamic therapy (PDT) and its clinical utilization. Herein, we engineered bioluminescent bacteria by transforming attenuated Salmonella typhimurium strain ΔppGpp (S.T. ΔppGpp) with firefly-luciferase-expressing plasmid (Luc-S.T.ΔppGpp) as an internal light source to evenly illuminate whole tumors. Upon being fixed inside tumors with in-situ formed hydrogel, the colonized Luc-S.T.ΔppGpp together with D-luciferin could continuously generate light to excite photosensitizer chlorin e6 (Ce6), leading to effective suppression of different types of tumors including opaque melanoma and large rabbit tumors. Such bioluminescence-triggered PDT presented significant advantages over conventional PDT excited with an external 660-nm light, which at a much high light energy could only slightly retard the growth of small subcutaneous tumors. Furthermore, we uncovered that Luc-S.T.ΔppGpp boosted PDT could also elicit potent antitumor immunity post the treatment to inhibit tumor metastasis and prevent tumor challenge. Therefore, this work highlights that such bioluminescent bacteria boosted PDT is a general and highly effective therapeutic approach toward diverse cancers with varying light-absorbing capacities and tumor sizes, promising for potential clinical translation because of their acceptable safety profiles. [ABSTRACT FROM AUTHOR]

Relieving tumor hypoxia has recently been found to be a promising approach to reverse tumor immunosuppression and thus enhance the treatment outcomes of diverse cancer treatments. Herein, we prepared a type of fluorinated covalent conjugate polymers (COPs) with sonosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) and perfluorosebacic acid (PFSEA) as cross-linkers, yielding THPP pf -COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPP pf -COPs could not only attenuate tumor hypoxia, but also exhibit the most effective suppression effect on tumor growth in the presence of ultrasound exposure by inducing immunogenic cell death of cancer cells. Furthermore, we found that the sonodynamic therapy of PFCE@THPP pf -COPs together with anti-CD47 immunotherapy would synergistically suppress tumor growth by increasing the tumor-infiltrating frequencies of phagocytic M1 macrophages and cytotoxic CD3+CD8+ T cells, while reducing the frequency of immunosuppressive regulatory T cells. Moreover, such combination treatment could also elicit potent protective memory antitumor immunity to prevent tumor challenge. Therefore, this work presents PFCE@THPP pf -COPs are a type of multifunctional nano-sonosensitizers potent in removing negative impacts of inherent tumor hypoxia and immunosuppression, and suppressing tumor growth and tumor recurrence by priming host's antitumor immunity, particularly in synergizing with anti-CD47 immunotherapy. [ABSTRACT FROM AUTHOR]

Gallium indium (GaIn) alloy as a kind of liquid metal (LM) with unique chemical and physical properties has attracted increasing attention for its potential biomedical applications. Herein, a series of core-shell GaIn@Metal (Metal: Pt, Au, Ag, and Cu) heterogeneous nanoparticles (NPs) are obtained by a simple in-situ reduction method. Take core-shell GaIn@Pt NPs for example, the synthesized GaIn@Pt NPs after Pt growth on their surface showed significantly improved photothermal conversion efficiency (PCE) and thermal stability under near-infrared (NIR) II light irradiation. Moreover, the core-shell GaIn@Pt NPs also exhibited good Fenton-like catalytic effect due to the presence of Pt on their surface, and could convert tumor endogenous H 2 O 2 to generate reactive oxygen species (ROS) for cancer cell killing. With biocompatible polyethylene glycol (PEG) modification, such GaIn@Pt-PEG NPs showed efficient tumor homing after intravenous injection, and could lead to effective NIR II triggered photothermal-chemodynamic synergistic therapy of tumors as evidenced in a mouse tumor model. Our work highlights the ingenious use of the chemical properties of metals, providing a rather simple route for the surface engineering of LM-based multifunctional nanoplatforms to achieve a variety of functionalities. Core-shell GaIn@Pt heterogeneous NPs prepared by in-situ reduction method were used for photothermal-enhanced catalytic therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis, a syndrome of acute organ dysfunction induced by various infections, could lead to a very high mortality in hospitals despite the development of advanced medical technologies. Herein, a type of two-phase releasing immune-stimulating composite is developed by mixing alginate (ALG) with muramyl dipeptide (MDP) and the nanoparticle formulation of monophosphoryl lipid A (MPLA), the latter two are immunomodulatory agents with different release rates from the formed ALG hydrogel. The obtained two phase-releasing composite could provide instantaneous sepsis protection by the rapid release of MDP to enhance the phagocytic and bactericidal function of macrophages. Later on, such composite could further offer long-term sepsis protection by the sustained release of MPLA to continuously activate the immune system, via up-regulating the production of various pro-inflammatory cytokines, promoting the polarization of macrophages, and increasing the percent of natural killer (NK) cells in the lesion after sepsis challenge. Mice survived from sepsis challenge after such treatment could resist a second infection. Notably, treatment with our composite could increase the mouse survival rate in a cecal ligation and puncture (CLP) induced polymicrobial sepsis model. This work provides an easy-translatable immune-stimulating formulation for effective protection against sepsis under various triggering causes. Our strategy may be promising for long-term broad prevention against various infections, and could potentially be used to protect medical workers under a new pandemic before a reliable vaccine is available. [Display omitted] [ABSTRACT FROM AUTHOR]