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.

Traditional cancer-therapeutic modalities such as chemotherapy suffer from the low therapeutic efficiency and severe side effects. The emerging nanocatalytic therapy could in-situ catalyze the endogenous substances into highly toxic species and then efficiently kill the cancer cells, but the lack of high-performance nanocatalysts hinders their broad clinical translation. In this work, we have successfully developed, for the first time, nanosized zero-valence crystalized iron nanoparticles for in-situ triggering nanocatalytic Fenton reaction within tumor microenvironment to produce large amounts of hydroxyl radicals and subsequently kill the cancer cells, which could be further synergistically enhanced by either photonic hyperthermia or magnetic hyperthermia as assisted by these iron nanoparticles acting as photothermal-conversion or magnetothermal-conversion nanoagents, respectively. Especially, the excellent magnetic performance of these zero-valence crystallized iron nanoparticles has achieved both in vitro and in vivo contrast-enhance magnetic resonance imaging for potentially guiding the photonic/magnetic hyperthermia-synergistic nanocatalytic cancer therapy. This work not only provides the new type of iron-based nanoparticles for biomedical application, but also demonstrates the high efficiency of nanocatalytic cancer therapy as assisted by both photonic and magnetic hyperthermia.

Cancer vaccines for prevention and treatment of tumors have attracted tremendous interests as a type of cancer immunotherapy strategy. A major challenge in achieving robust T-cell responses to destruct tumor cells after vaccination is the abilities of antigen cross-presentation for antigen-presenting cells (APCs) such as dendritic cells (DCs). Herein, we demonstrate that a polyamidoamine dendrimer modified with guanidinobenzoic acid (DGBA) could serve as an effective protein carrier to enable delivery of protein antigen, thereby leading to effective antigen cross-presentation by DCs. With ovalbumin (OVA) as the model antigen and unmethylated cytosine-guanine dinucleotides (CpG) as the adjuvant, a unique type of tumor vaccine is formulated. Importantly, such DGBA-OVA-CpG nanovaccine can induce robust antigen-specific cellular immunities and further demonstrates outstanding prophylactic efficacy against B16-OVA melanoma. More significantly, the nanovaccine shows excellent therapeutic effect to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1) checkpoint-blockade immunotherapy. This study presents the great promises of employing rationally engineered cytosolic protein carriers for the development of tumor vaccines to achieve effective cancer immunotherapy.

Overexpression of P-glycoprotein (P-gp), which is responsible for pumping chemotherapeutic drugs out of tumor cells, has been recognized as an important cause of drug resistance in conventional chemotherapy. Herein, porous platinum nanoparticles (pPt NPs) are developed to enable the combined electrodynamic therapy (EDT) with chemotherapy. With polyethylene glycol (PEG) coating, the obtained pPt-PEG NPs could be loaded with anticancer drug doxorubicin (DOX) by utilizing the porous structure of pPt NPs. Those pPt-PEG NPs are able to produce reactive oxygen species (ROS) by triggering water decomposition under electric field, independent of O2 and H2O2 contents in the tumor. Furthermore, the ROS generated during EDT could induce the inhibition of P-glycoprotein (P-gp), in turn enhancing the efficacy of chemotherapeutic agents by facilitating intracellular accumulation of drugs. As the results, excellent synergetic therapeutic effects were observed by combining chemotherapy with EDT using DOX-loaded pPt (DOX@pPt-PEG) NPs, as demonstrated by both in vitro and in vivo experiments. This study demonstrates a new concept of combinational cancer therapy with superior therapeutic efficacy.

High expression of indoleamine 2,3-dioxygenase 1 (IDO1) is a major cause of tumor induced immunosuppression, and appears to be associated with poor prognosis in human colorectal cancer and some others. In this study, we construct a bifunctional liposome by self-assembly of oxaliplatin-prodrug (Oxa(IV)) conjugated phospholipid and alkylated NLG919 (aNLG), an IDO1 inhibitor, together with other commercial lipids. The obtained aNLG/Oxa(IV)-Lip can not only release cytotoxic oxaliplatin inside the reductive cytosol to trigger immunogenic cell death (ICD) of cancer cells, but also efficiently retard the degradation of tryptophan to immunosuppressive kynurenine via the NLG919 mediated inhibition of IDO1. Moreover, in vivo pharmacokinetic studies indicate that such aNLG/Oxa(IV)-Lip has a long blood circulation time, thereby enables highly-efficient passive tumor homing. Upon tumor accumulation, such aNLG/Oxa(IV)-Lip presents superior synergistic antitumor efficacies to both subcutaneous and orthotopic CT26 tumors, ascribing to significantly primed anti-tumor immunity of enhanced intratumoral infiltration of CD8+ T cells, scretion of cytotoxic cytokines and downregulation of immunosuppressive regulatory T cells. This work highlights that such bifunctional aNLG/Oxa(IV)-Lip is a potent candidate for future clinical translation owing to its excellent biocompatibility and high therapeutic efficacy.

A general therapeutic strategy to treat breast cancer is attractive as different subtypes of breast cancers often exhibit distinct response to existing cancer therapeutics. To this end, we prepare a catalyst couple of glucose oxidase (GOx) and gallic acid-ferrous (GA-Fe) nanocomplexes, a type of near-infrared (NIR) absorbing Fenton catalyst, to enable NIR-trigger in-situ gelation and enhanced chemodynamic/starvation therapy that appears to be effective for different types of breast cancer cells. In this system, GOx is mixed with GA-Fe in a solution of N,N-dimethylacrylamide (DMAA) and poly (ethylene glycol) double acrylate (PEGDA). Upon intratumoral injection and NIR laser exposure, such GA-Fe show rapid temperature increase, which would simultaneously increase the catalytic efficiencies of GA-Fe and GOx. The cascade production of hydroxyl radicals (•OH) from glucose is then initiated to enable polymerization of DMAA and PEGDA to form a hydrogel at the injection site within the tumor. The continuous production of cytotoxic •OH together with glucose depletion by the intratumorally fixed catalyst couple would further confer effective destruction of breast cancer tumors by such chemodynamic/starvation therapy. Our work presents a hydrogel-based therapeutic strategy for local treatment of solid tumors with high tumor destruction efficacy and low systemic toxicity.

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 THPPpf-COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPPpf-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@THPPpf-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@THPPpf-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.

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)SA2) and carboxyl group terminated PEG (PEG5k-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.

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.

Tumor ablation therapies provide a minimally invasive approach to treat cancer. However, inhibition of cancer metastasis and recurrence after ablation is still a challenge in clinical trials. Here, we propose a strategy using combinatorial thermal ablation, adjuvants and immune checkpoint blockade (ICB) to inhibit metastatic tumor and recurrence via antitumor immune responses post tumor thermal ablation, which are frequently used in the clinic. Furthermore, a strong immune memory against cancer was observed 80 days after the primary tumor was ablated. Considering that all components in our design are approved by Food and Drug Administration (FDA), we provide a strategy based on clinically used cancer treatment technique that is promising in clinical translation.

Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H2O2. Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H2O2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with banoxantrone dihydrochloride (AQ4N), a hypoxia-activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co-deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment.

Although graphene oxide (GO) has recently been considered as a highly attractive nanomaterial for future cancer imaging and therapy, it is still a major challenge to improve its in vivo tumor active targeting efficiency. Here in this full article, we demonstrated the successful and significantly enhanced in vivo tumor vasculature targeting efficacy of well-functionalized GO nanoconjugates by using vascular endothelial growth factor 121 (VEGF121) as the targeting ligand. As-developed GO nanoconjugate exhibits excellent in vivo stability, specific in vitro and in vivo vascular endothelial growth factor receptor (VEGFR) targeting, significantly enhanced tumor accumulation (>8 %ID/g) as well as high tumor-to-muscle contrast, showing great potential for future tumor targeted imaging and therapy.

Bacterial infection has been a great threat to dermal wounds, especially to difficult-to-heal diabetic wounds. It is known that reactive oxygen species (ROS) generated by wounds or bacterial infection could further impede wound healing. Here, a type of ROS-scavenging hydrogel is developed by using polyvinyl alcohol (PVA) cross-linked by a ROS-responsive linker. The obtained hydrogel could act as an effective ROS-scavenging agent to promote the wound closure by decreasing the ROS level and up-regulating M2 phenotype macrophages around the wound. Importantly, such hydrogel formed in the wound could allow release of therapeutics, including mupirocin to kill bacteria, and granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate the wound closure, in responsive to endogenous ROS existing in the wound microenvironment. Remarkably, our drug-loaded ROS-scavenging hydrogel could be employed to effectively treat various types of wounds including difficult-to-heal diabetic wounds with bacterial infection. Therefore, this work presents an effective strategy based on ROS-scavenging hydrogel for wound healing under various kinds of complications.

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt-CHO-PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt-CHO-PEG shows "stealth-like" long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt-CHO-PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ, allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs.

Nanoscale outer membrane vesicles (OMVs) secreted by Gram-negative bacteria are often applied in antibacterial treatment as adjuvants or antigens. Recently, OMVs have also been tested in a few anti-tumor treatment studies, in which OMVs are injected multiple times to achieve certain therapeutic effects, showing risks in repeated cytokine storms. Herein, we propose the use a single low dose of OMVs combined with photothermal therapy (PTT) for effective cancer treatment. It was found that single i. v. injection of OMVs could activate the immune system by boosting the secretion levels of anti-tumor related cytokines. In addition, single i. v. injection of OMVs could also lead to extravasation of red blood cells in the tumor mainly owing to the effect of lipopolysaccharide on the OMVs. Such effect was not observed in other normal organs. As the results, the tumors on OMV-treated mice showed obviously darkened color with greatly increased intratumoral optical absorbance in the near-infrared (NIR) region, further enabling effective photothermal ablation of those tumors by the NIR laser. Without causing obvious adverse responses, bacteria-derived OMVs may be a new type of therapeutic agent for cancer treatment with multiple functions.

The limited tumor specific uptake of nanoparticles is one of major bottlenecks for clinical translation of nanoscale therapeutics. Herein, we propose a strategy using internal radioisotope therapy (RIT) delivered by liposomal nanoparticles to improve the tumor vasculature permeability, so as to increase the tumor specific uptake of the second-wave therapeutic nanoparticles for enhanced cancer therapies. Via a convenient method, a therapeutic radioisotope iodine-131 is labeled onto albumin-encapsulated liposomes with greatly improved radiolabeling stability compared to 131I labeled albumin. The obtained 131I-liposome with long blood half-life could accumulate in the tumor and damage tumor blood endothelial cells to improve the tumor vascular permeability. As the result, the tumor retention of the second wave of liposomal nanoparticles could be greatly increased owing to the RIT-enhanced EPR effect. In three separated experiments, we then demonstrate that such strategy could be utilized for photothermal therapy (PTT), hypoxia-activated chemotherapy (HCT) and checkpoint blockade immunotherapy, all of which could be enhanced by RIT with excellent in vivo synergistic therapeutic outcomes. Our work highlights the great promises of employing nanoparticle-mediated RIT to modulate tumor vasculature for further enhanced cancer therapy, and may have potential value for clinical translation.

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.

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.