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Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu 2+ ) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu 2+ and help to achieve photothermal therapy. Afterward, the released Cu 2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Active polymetallic atomic clusters can initiate heterogeneous catalytic reactions in the tumor microenvironment, and the products tend to cause manifold damage to cell metabolic functions. Herein, bimetallic PtPd atomic clusters (BAC) are constructed by the stripping of Pt and Pd nanoparticles on nitrogen-doped carbon and follow-up surface PEGylation, aiming at efficacious antineoplastic therapy through heterogeneous catalytic processes. After endocytosed by tumor cells, BAC with catalase-mimic activity can facilitate the decomposition of endogenous H 2 O 2 into O 2 . The local oxygenation not only alleviates hypoxia to reduce the invasion ability of cancer cells but also enhances the yield of • O 2 - from O 2 catalyzed by BAC. Meanwhile, BAC also exhibit peroxidase-mimic activity for • OH production from H 2 O 2 . The enrichment of reactive oxygen species (ROS), including the radicals of • OH and • O 2 - , causes significant oxidative cellular damage and triggers severe apoptosis. In another aspect, intrinsic glutathione (GSH) peroxidase-like activity of BAC can indirectly upregulate the level of lipid peroxides and promote ferroptosis. Such deleterious redox dyshomeostasis caused by ROS accumulation and GSH consumption also results in immunogenic cell death to stimulate antitumor immunity for metastasis suppression. Collectively, this paradigm is expected to inspire more facile designs of polymetallic atomic clusters in disease therapy.

Traditional Fe-based Fenton reaction for inducing oxidative stress is restricted by random charge transfer without oriental delivery, and the resultant generation of reactive oxygen species (ROS) is always too simplistic to realize a satisfactory therapeutic outcome. Herein, FeN v /CN nanosheets rich in nitrogen vacancies are developed for high-performance redox dyshomeostasis therapy after surface conjugation with polyethylene glycol (PEG) and cyclic Arg-Gly-Asp (cRGD). Surface defects in FeN v /CN serve as electron traps to drive the directional transfer of the excited electrons to Fe atom sites under ultrasound (US) actuation, and the highly elevated electron density promote the catalytic conversion of H 2 O 2 into ·OH. Meanwhile, energy band edges of FeN v /CN favor the production of 1 O 2 upon interfacial redox chemistry, which is enhanced by the optimal separation/recombination dynamics of electron/hole pairs. Moreover, intrinsic peroxidase-like activity of FeN v /CN contributes to the depletion of reductant glutathione (GSH). Under the anchoring effect of cRGD, PEGylated FeN v /CN can be efficiently enriched in the tumorous region, which is ultrasonically activated for concurrent ROS accumulation and GSH consumption in cytosolic region. The deleterious redox dyshomeostasis not only eradicates primary tumor but also suppresses distant metastasis via antitumor immunity elicitation. Collectively, this study could inspire more facile designs of chalybeates for medical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Intracellular redox homeostasis plays an important role in promoting tumor progression, development and even treatment resistance. To this end, redox balance impairment may become a prospective therapeutic target of cancer. Herein, a manganese-based homeostasis modulator (MHS) is developed for inducing severe reactive oxygen species accumulation and glutathione (GSH) deprivation, where such redox dyshomeostasis brings about dramatic ferroptosis/apoptosis. Tumor-specific degradation of manganese oxide nanocarriers contributes to hypoxia alleviation and loaded cargo release, resulting in apoptosis by augmented sonodynamic therapy and chemodynamic therapy. On the other hand, regional oxygenation significantly downregulates the expression of activating transcription factor 4, which can synergize with the released sulfasalazine to inhibit the downstream cystine antiporter xCT. Biosynthesis of GSH is sufficiently interrupted by the xCT suppression, leading to the reduction of glutathione peroxidase 4 (GPx4) level. The resultant excessive lipid peroxides promote intense ferroptosis to motivate cell death. On this basis, splendid treatment outcome by MHS is substantiated both in vitro and in vivo, thanks to the synergy of antitumor immunity elicitation. Taken together, this paradigm provides an insightful strategy to evoke drastic ferroptosis/apoptosis toward therapeutics and may also expand the eligibility of manganese-derived nanoagents for medical applications., (© 2023 Wiley-VCH GmbH.)

Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca 2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor-targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel-oxaliplatin is rationally synthesized, which can be covalently self-assembled with diselenide-containing cross-linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on-target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined αPD-1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long-term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual-responsive diselenide-based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy., (© 2022 Wiley-VCH GmbH.)

Immune checkpoint blockade (ICB) therapy shows excellent efficacy against malignancies; however, insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (TME) are considered as the two major stumbling blocks to a broad ICB response. Here, a combinational therapeutic strategy is reported, wherein TME-reactive oxygen species/pH dual-responsive signal transducers and activators of transcription 3 inhibitor nanoprodrugs MPNPs are combined with oncolytic herpes simplex virus 1 virotherapy to synergistically ignite pyroptosis for enhancing immunotherapy. MPNPs exhibit a certain level of tumor accumulation, reduce tumor cell stemness, and enhance antitumor immune responses. Furthermore, the simultaneous application of oncolytic viruses (OVs) confers MPNPs with higher tumor penetration capacity and remarkable gasdermin-E-mediated pyroptosis, thereby reshaping the TME and transforming "cold" tumors into "hot" ones. This "fire of immunity" strategy successfully activates robust T-cell-dependent antitumor responses, potentiating ICB effects against local recurrence and pulmonary metastasis in preclinical "cold" murine triple-negative breast cancer and syngeneic oral cancer models. Collectively, this work may pave a new way and offer an unprecedented opportunity for the combination of OVs with nanomedicine for cancer immunotherapy., (© 2023 Wiley-VCH GmbH.)

Intracellular redox dyshomeostasis promoted by tumor microenvironment (TME) modulation has become an appealing therapeutic target for cancer management. Herein, a dual plasmonic Au/SF@Cu 2-x S nanoreactor (abbreviation as ASC) is elaborately developed by covalent immobilization of sulfur defective Cu 2-x S nanodots onto the surface of silk fibroin (SF)-capped Au nanoparticles. Tumor hypoxia can be effectively alleviated by ASC-mediated local oxygenation, owing to the newfound catalase-mimic activity of Cu 2-x S. The semiconductor of Cu 2-x S with narrow bandgap energy of 2.54 eV enables a more rapid dissociation of electron-hole (e - /h + ) pair for a promoted US-triggered singlet oxygen ( 1 O 2 ) generation, in the presence of Au as electron scavenger. Moreover, Cu 2-x S is devote to Fenton-like reaction to catalyze H 2 O 2 into ·OH under mild acidity and simultaneously deplete glutathione to aggravate intracellular oxidative stress. In another aspect, Au nanoparticles with glucose oxidase-mimic activity consumes intrinsic glucose, which contributes to a higher degree of oxidative damage and energy exhaustion of cancer cells. Importantly, such tumor starvation and 1 O 2 yield can be enhanced by Cu 2-x S-catalyzed O 2 self-replenishment in H 2 O 2 -rich TME. ASC-initiated M1 macrophage activation and therapy-triggered immunogenetic cell death (ICD) favors the systematic tumor elimination by eliciting antitumor immunity. This study undoubtedly enriches the rational design of SF-based nanocatalysts for medical utilizations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Immunotherapy is one of the most promising clinical modalities for the treatment of malignant tumors and has shown excellent therapeutic outcomes in clinical settings. However, it continues to face several challenges, including long treatment cycles, high costs, immune-related adverse events, and low response rates. Thus, it is critical to predict the response rate to immunotherapy by using imaging technology in the preoperative and intraoperative. Here, the latest advances in nanosystem-based biomaterials used for predicting responses to immunotherapy via the imaging of immune cells and signaling molecules in the immune microenvironment are comprehensively summarized. Several imaging methods, such as fluorescence imaging, magnetic resonance imaging, positron emission tomography imaging, ultrasound imaging, and photoacoustic imaging, used in immune predictive imaging, are discussed to show the potential of nanosystems for distinguishing immunotherapy responders from nonresponders. Nanosystem-based biomaterials aided by various imaging technologies are expected to enable the effective prediction and diagnosis in cases of tumors, inflammation, and other public diseases., (© 2022 Wiley-VCH GmbH.)

Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second-stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)-mediated pyroptosis to enhance the immunological response. In combination with anti-PD-1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high-efficiency immune checkpoint blockade therapy., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO 2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO 2- x . Compared to 3.09 eV of nano-ZrO 2- x , the bandgap of ZrO 2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e - /h + separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen ( 1 O 2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O 2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals ( • R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives., (© 2022 Wiley-VCH GmbH.)

To date, the construction of heterogeneous interfaces between sonosensitizers and other semiconductors or noble metals has aroused increasing attention, owing to an enhanced interface charge transfer, augmented spin-flip, and attenuated activation energy of oxygen. Here, a smart therapeutic nanoplatform is constructed by surface immobilization of glucose oxidase (GOx) onto a TiO 2 @Pt Schottky junction. The sonodynamic therapy (SDT) and starvation therapy (ST) mediated by TiO 2 @Pt/GOx (TPG) promote systemic tumor suppression upon hypoxia alleviation in tumor microenvironment. The band gap of TiO 2 @Pt is outstandingly decreased to 2.9 eV, in contrast to that of pristine TiO 2 . The energy structure optimization enables a more rapid generation of singlet oxygen ( 1 O 2 ) and hydroxyl radicals ( • OH) by TiO 2 @Pt under ultrasound irradiation, resulting from an enhanced separation of hole-electron pair for redox utilization. The tumorous reactive oxygen species (ROS) accumulation and GOx-mediated glucose depletion facilitate oxidative damage and energy exhaustion of cancer cells, both of which can be tremendously amplified by Pt-catalyzed oxygen self-supply. Importantly, the combinatorial therapy triggers intense immunogenetic cell death, which favors a follow-up suppression of distant tumor and metastasis by evoking antitumor immunity. Collectively, this proof-of-concept paradigm provides an insightful strategy for highly efficient SDT/ST, which possesses good clinical potential for tackling cancer.

Endogenous H 2 O 2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H 2 O 2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H 2 O 2 -rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn 2+/3+ . The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O 2 replenishment through Pt-catalyzed decomposition of H 2 O 2 . Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn 2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H 2 O 2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H 2 O 2 balance during H 2 O 2 -depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Recent years have witnessed increasingly rapid advances in nanocarrier-based biomedicine aimed at improving treatment paradigms for cancer. Nanogels serve as multipurpose and constructed vectors formed via intramolecular cross-linking to generate drug delivery systems, which is attributed predominantly to their satisfactory biocompatibility, bio-responsiveness, high stability, and low toxicity. Recently, immunotherapy has experienced unprecedented growth and has become the preferred strategy for cancer treatment, and mainly involves the mobilisation of the immune system and an enhanced anti-tumour immunity of the tumour microenvironment. Despite the inspiring success, immunotherapeutic strategies are limited due to the low response rates and immune-related adverse events. Like other nanomedicines, nanogels are comparably limited by lower focal enrichment rates upon introduction into the organism via injection. Because nanogels are three-dimensional cross-linked aqueous materials that exhibit similar properties to natural tissues and are structurally stable, they can comfortably cope with shear forces and serum proteins in the bloodstream, and the longer circulation life increases the chance of nanogel accumulation in the tumour, conferring deep tumour penetration. The large specific surface area can reduce or eliminate off-target effects by introducing stimuli-responsive functional groups, allowing multiple physical and chemical modifications for specific purposes to improve targeting to specific immune cell subpopulations or immune organs, increasing the bioavailability of the drug, and conferring a low immune-related adverse events on nanogel therapies. The slow release upon reaching the tumour site facilitates long-term awakening of the host's immune system, ultimately achieving enhanced therapeutic effects. As an effective candidate for cancer immunotherapy, nanogel-based immunotherapy has been widely used. In this review, we mainly summarize the recent advances of nanogel-based immunotherapy to deliver immunomodulatory small molecule drugs, antibodies, genes and cytokines, to target antigen presenting cells, form cancer vaccines, and enable chimeric antigen receptor (CAR)-T cell therapy. Future challenges as well as expected and feasible prospects for clinical treatment are also highlighted.

Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe 2+ /Fe 3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo., Competing Interests: Declaration of Competing Interest We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Here, acidic tumor microenvironment (TME)-responsive nano-Bi 2 Se 3 @MnCaP, as a near-infrared-II (NIR-II) biowindow-triggered free radical generator for hypoxia-irrelevant phototherapy, is elaborately developed by biomimetic mineralization of MnCaP onto 2, 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH)-loaded mesoporous nano-Bi 2 Se 3 to form Bi 2 Se 3 /AIPH@MnCaP (BAM). Surface mineral of MnCaP can be degraded under mild acidity, leading to the release of both Mn 2+ and AIPH. The leached Mn 2+ not only facilitates chemodynamic therapy (CDT) via hydroxyl radicals ( • OH) from Mn 2+ -mediated Fenton-like reaction but also acts as contrast agent for magnetic resonance imaging. In another aspect, the splendid photothermal conversion capacity of BAM enables a rapid hyperthermia generation under NIR-II laser irradiation for photothermal therapy (PTT). Simultaneously, the local thermal shock can induce the disintegration of AIPH to generate alkyl radicals ( • R) for thermodynamic therapy (TDT) and accelerate Fenton-like reaction rate to augment CDT efficacy. The strong synergistic effects from cooperative CDT/PTT/TDT are applied to 4T1 tumor suppression with minimal side effects. Importantly, the combination therapy can effectively trigger immunogenetic cell death and enhance antitumor immunity for systemic tumor eradication. Collectively, this proof-of-concept study demonstrates a more efficacious and safer strategy for oxygenation-independent phototherapy, which holds a good potential for clinical translation in cancer management., (© 2021 Wiley-VCH GmbH.)

It remains a conundrum to reconcile the contradiction between effective tumor retention and deep intratumor infiltration for nanotherapeutics due to the sophisticated drug delivery journey. Herein, we reported an acid-sensitive supramolecular nanoassemblies (DCD SNs) based on the multivalent host-gest inclusions of two polymer conjugates for conquering diverse physiological blockages and amplifying therapeutic efficacy. The multiple inclusions of repetitive units on the hydrophilic polymer backbone reinforced the binding affinity and induced robust self-assembly, ameliorating instability of the self-assemblies and facilitating to prolong the drug retention time. By virtue of the acid-sensitive Schiff base linkages, the supramolecular nanoassembly could respond to the unique tumor microenvironment (TME), dissociate, and transform into smaller particles (∼30 nm), thereby efficiently traversing the complicated extracellular matrix and irregular blood vessels to achieve deep intratumor infiltration. The acid-sensitive DCD SNs can absorb a large number of protons in the acidic lysosomal environment, causing the proton sponge effect, which was conducive to their escape from endolysosomes and accelerated lysosomal disruption, so that the active chemotherapeutic doxorubicin (DOX) could enter the nucleus well and exert severe DNA damage to induce apoptosis. This versatile supramolecular nanoplatform is anticipated to be a promising candidate to overcome the limitations of insufficient stability within the circulation and weak intratumor penetration.

A hypoxic and acidic tumor microenvironment (TME) plays a significant role in cancer development through complex cellular signaling networks, and it is thus challenging to completely eradicate tumors via monotherapy. Here, PEGylated CoFe 2 O 4 nanoflowers (CFP) with multiple enzymatic activities, serving as bioreactors responsive to TME cues, were synthesized via a typical solvothermal method for augmented sonodynamic therapy (SDT) and chemodynamic therapy (CDT) with elicitation of robust immune response. The CFP occupying multivalent elements (Co 2+/3+ , Fe 2+/3+ ) exhibited strong Fenton-like and catalase-like activity. In another aspect, CFP itself is a brand-new sonosensitizer for high-performance SDT based on ultrasound-triggered electron (e - )/hole (h + ) pair separation from the energy band with promptness and high efficiency. With efficient enrichment in tumorous tissue as revealed by magnetic resonance imaging, CPF could generate • OH for CDT relying on Fenton-like reactions. Moreover, catalase-mimicking CFP could react with endogenous H 2 O 2 to generate molecular oxygen, and high O 2 level may promote the production of 1 O 2 for SDT. What's more, the reactive oxygen species obtained from combined SDT/CDT could efficiently trigger immunogenic cell death through a synergistic therapy based on the elicitation of antitumor immunity with the aid of an immune checkpoint blockade for the sake of suppressing primary and distant tumors as well as lung metastasis. Taken together, this paradigm delivers useful insights for developing in-coming nanocomposites based on cobalt ferrite for cancer theranostics.

Nano-zirconia, as an amphoteric semiconductor, has been industrially exploited in photocatalytic reactions and as piezoelectric sensors. However, its biomedical applications, especially in antitumor therapeutics, have been seldom investigated to date. Here, oxygen-deficient zirconia (ZrO 2-x )-based nanoplatform with surface PEGylation and cyclic-Arg-Gly-Asp (cRGD) peptide functionalization (ZrO 2-x @PEG/cRGD, abbreviated as ZPR) was rationally designed and established for the first time, which was utilized as therapy-activated "immunogenic cell death (ICD)" inducer to boost photothermal-augmented sonodynamic tumor elimination in NIR-II biological window. As-synthesized ZPR nanoparticles (NPs) exhibited intense optical absorbance in the wavelength range of 900-1100 nm, which endowed ZPR NPs with a photothermal conversion efficiency as high as 45.8% for photothermal therapy (PTT). Moreover, owing to the abundant surface oxygen defects, ZPR NPs can serve as a category of high-performance nano-sonosensitizer based on the strengthened separation of electron (e - )/hole (h + ) pairs from the energy band under external ultrasound (US) activation. More importantly, cytotoxic reactive oxygen species (ROS) generated from sonodynamic therapy (SDT) can effectively induce immunogenic cell death (ICD), which is regarded to be significant to boost systemic anti-tumor immunity for rendering a complete tumor eradication post-treatment. In vivo experiments on tumor xenografts demonstrated the high therapeutic efficacy upon photothermal-augmented sonodynamic therapy, with the aid of photoacoustic (PA) imaging navigation. Remarkably, the level of inflammatory cytokines, including type I interferon (IFN), tumor necrosis factor α (TNF-α) as well as interleukin (IL-6) were systemically upgraded after NIR-II/US irradiation, verifying the promotion of immunogenicity. Taken together, this study delivers useful insights for extending the applications of zirconia as promising translational medicine for tumor theranostics in the near future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ferroptosis therapy, which applies ferroptotic inducers to produce lethal lipid peroxidation and induce the death of tumor cells, is regarded as a promising therapeutic strategy for cancer treatment. However, there is still a challenge regarding how to increase reactive oxygen species (ROS) accumulation in the tumor microenvironment (TME) to enhance antitumor efficacy. Herein, we designed a nanosystem coated with the FDA approved poly(lactic-co-glycolic acid) (PLGA) containing ferrous ferric oxide (Fe3O4) and chlorin E6 (Ce6) for synergistic ferroptosis-photodynamic anticancer therapy. The Fe3O4-PLGA-Ce6 nanosystem can dissociate in the acidic TME to release ferrous/ferric ions and Ce6. Then, the Fenton reaction between the released ferrous/ferric ions and intracellular excess hydrogen peroxide can occur to produce hydroxyl radicals (˙OH) and induce tumor cell ferroptosis. The released Ce6 can increase the generation and accumulation of ROS under laser irradiation to offer photodynamic therapy, which can boost ferroptosis in 4T1 cells. Moreover, magnetic monodisperse Fe3O4 loading provides excellent T2-weighted magnetic resonance imaging (MRI) properties. The Fe3O4-PLGA-Ce6 nanosystem possesses MRI ability and highly efficient tumor suppression with high biocompatibility in vivo due to the synergism of photodynamic and ferroptosis antitumor therapies.

Background: With increased specialization of health care services and high levels of patient mobility, accessing health care services across multiple hospitals or clinics has become very common for diagnosis and treatment, particularly for patients with chronic diseases such as cancer. With informed knowledge of a patient's history, physicians can make prompt clinical decisions for smarter, safer, and more efficient care. However, due to the privacy and high sensitivity of electronic health records (EHR), most EHR data sharing still happens through fax or mail due to the lack of systematic infrastructure support for secure, trustable health data sharing, which can also cause major delays in patient care., Objective: Our goal was to develop a system that will facilitate secure, trustable management, sharing, and aggregation of EHR data. Our patient-centric system allows patients to manage their own health records across multiple hospitals. The system will ensure patient privacy protection and guarantee security with respect to the requirements for health care data management, including the access control policy specified by the patient., Methods: We propose a permissioned blockchain-based system for EHR data sharing and integration. Each hospital will provide a blockchain node integrated with its own EHR system to form the blockchain network. A web-based interface will be used for patients and doctors to initiate EHR sharing transactions. We take a hybrid data management approach, where only management metadata will be stored on the chain. Actual EHR data, on the other hand, will be encrypted and stored off-chain in Health Insurance Portability and Accountability Act-compliant cloud-based storage. The system uses public key infrastructure-based asymmetric encryption and digital signatures to secure shared EHR data., Results: In collaboration with Stony Brook University Hospital, we developed ACTION-EHR, a system for patient-centric, blockchain-based EHR data sharing and management for patient care, in particular radiation treatment for cancer. The prototype was built on Hyperledger Fabric, an open-source, permissioned blockchain framework. Data sharing transactions were implemented using chaincode and exposed as representational state transfer application programming interfaces used for the web portal for patients and users. The HL7 Fast Healthcare Interoperability Resources standard was adopted to represent shared EHR data, making it easy to interface with hospital EHR systems and integrate a patient's EHR data. We tested the system in a distributed environment at Stony Brook University using deidentified patient data., Conclusions: We studied and developed the critical technology components to enable patient-centric, blockchain-based EHR sharing to support cancer care. The prototype demonstrated the feasibility of our approach as well as some of the major challenges. The next step will be a pilot study with health care providers in both the United States and Switzerland. Our work provides an exemplar testbed to build next-generation EHR sharing infrastructures., (©Alevtina Dubovitskaya, Furqan Baig, Zhigang Xu, Rohit Shukla, Pratik Sushil Zambani, Arun Swaminathan, Md Majid Jahangir, Khadija Chowdhry, Rahul Lachhani, Nitesh Idnani, Michael Schumacher, Karl Aberer, Scott D Stoller, Samuel Ryu, Fusheng Wang. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.08.2020.)

Hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) are advantageous for loading small-molecule therapeutic drugs coupled with photothermal ablation for synergistic tumor therapy. However, treatment efficacy mediated by HMCuS NPs is not always satisfactory owing to their insensitivity toward the tumor microenvironment (TME), and unpredictable drug leakage may also result in deleterious systemic toxicity. Here, a novel HMCuS@MnO 2 -based core-shell nanoplatform was developed as a highly efficient TME modulator, which could alleviate tumor hypoxia, deplete the level of intracellular glutathione (GSH) and trigger the dissolution of Mn 2+ . Moreover, MnO 2 , in situ grown on the surface of HMCuS, may act as a gatekeeper by forming a stimulus-responsive plug within the mesoporous structure, which effectively prevented the premature release of encapsulated photosensitizer chlorin e6 (Ce6) and was responsive to the acidic TME for demand-based drug release. Under the condition of 660/808 nm dual-wavelength laser irradiation, hyperthermia-mediated photothermal therapy (PTT) and reactive oxygen species (ROS)-mediated photodynamic therapy (PDT) can be triggered for tumor eradication, which were further enhanced upon the modification of the TME. In the meantime, splendid photoacoustic (PA)/fluorescence (FL)/magnetic resonance (MR) imaging properties of HMCuS@MnO 2 /Ce6 (CMC) NPs could enable the realization of more precise, reliable and on-demand combination therapy. In a word, this study illustrated a promising approach to strengthen the efficacy of HMCuS-based nanotherapeutics, which would definitely promote the further exploitation of smarter nanoplatforms for synergistic disease management.

Nanoparticle-based tumor immunotherapy has emerged to show great potential for simultaneously regulating the immunosuppressive tumor microenvironment, reducing the unpleasant side effects, and activating tumor immunity. Herein, an excipient-free glutathione/pH dual-responsive prodrug nanoplatform is reported for immunotherapy, simply by sequentially liberating 5-aminolevulinic acid and immunogenically inducing doxorubicin drug molecules, which can leverage the acidity and reverse tumor microenvironment. The obtained nanoplatform effectively boosts the immune system by promoting dendritic cell maturation and reducing the number of immune suppressive immune cells, which shows the enhanced adjunctive effect of anti-programmed cell death protein 1 therapy. Overall, the prodrug-based immunotherapy nanoplatform may offer a reliable strategy for improving synergistic antitumor efficacy., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Glucose oxidase (GOx)-mediated starvation circumvents the energy supply for tumor growth, which has been proved as a potent tumor treatment modality. However, tumor hypoxia negatively affects the efficacy of oxygen-involved glucose decomposition reaction. Moreover, curative effect via glucose depletion is not usually satisfactory enough and adjuvant remedies are always required for a promoted tumor ablation. Herein, a multifunctional nanoreactor based on hollow Bi 2 Se 3 nanoparticles was developed by loading oxygenated perfluorocarbon (PFC) and surface modification with GOx, which was exploited for an enhanced tumor starvation and highly sensitive photothermal therapy (PTT). GOx-mediated tumor starvation could impede the adenosine triphosphate (ATP) generation and further downregulate the expression of heat shock protein (HSP) to decrease the thermoresistance of cells. Afterwards, near infrared (NIR) laser irradiation was performed not only to trigger sensitized PTT but also to initiate the release of encapsulated oxygen to relieve local hypoxia. Then, such GOx-mediated tumor starvation would be further amplified, accompanying with secondary enhanced suppression of HSP. Both in vitro and in vivo investigations demonstrated that such nanoreactor can realize a fascinating therapeutic outcome with minimal adverse effects in virtue of the improved synergistic starvation therapy and PTT. Taken together, the proposed treatment paradigm may inspire the future development of more intelligent nanoplatforms toward high efficient cancer therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In spite of widespread applications of nano-photosensitizers, poor tumor penetration and severe hypoxia in the tumor microenvironment (TME) always result in an undesirable therapeutic outcome of photodynamic therapy (PDT). Herein, a biocompatible agarose-based hydrogel incorporated with sodium humate (SH), manganese oxide (MnO 2 ) and chlorin e6 (Ce6) was synthesized as agarose@SH/MnO 2 /Ce6 through a "co-trapped" strategy during a sol-gel process and employed for combined photothermal therapy (PTT) and enhanced PDT. NIR-induced local hyperthermia is responsible for not only activating Ce6 release, but also triggering the catalytic decomposition of H 2 O 2 mediated by MnO 2 to relieve hypoxia. Such a hybrid hydrogel can realize deep tissue penetration through intratumoral injection, and exhibit remarkable tumor-site retention. Moreover, programmed laser irradiation led to an extremely high tumor growth inhibition rate of 93.8% in virtue of enhanced PTT/PDT. In addition, ultralow systemic toxicity caused by the hybrid hydrogel was further demonstrated in vivo. This reliable and eco-friendly hydrogel paves the way for the development of smart gel-based biomaterials, which respond to both exogenous and endogenous stimuli, towards the management of cancer and other major diseases.

Theranostic nanoplatforms that integrate therapy and diagnosis in a single composite have become increasingly attractive in the field of precise and efficient tumor treatment. Herein, a novel oxygen-deficient zirconia (ZrO 2- x ) nanosystem based on the conjugation of thiol-polyethylene glycol-amine (SH-PEG-NH 2 ) and chlorin e6 (Ce6) was elaborately designed and established for efficacious photothermal/photodynamic therapy (PTT/PDT) and fluorescence/photoacoustic (FL/PA) bimodal imaging for the first time. The crystalline-disordered, PEGylated ZrO 2- x nanoparticles (ZP NPs) displayed strong optical absorption in the near-infrared (NIR) window and were featured with significant photothermal conversion capacity. The ZP NPs were further covalently conjugated with Ce6 to form ZrO 2- x @PEG/Ce6 (ZPC) NPs, which displayed a long circulatory half-life, efficient tumor accumulation, and outstanding FL/PA imaging performance. Moreover, the nanocomposites effectively generated cytotoxic intracellular reactive oxygen species (ROS) responsive to laser activation. Both cell studies and animal experiments explicitly demonstrated that ZPC NPs mediated remarkable tumor ablation with minimal systemic toxicity thanks to their tumor-specific PTT/PDT effect. Collectively, these findings may open up new avenues to broaden the application of oxygen-deficient ZrO 2- x nanostructures as high-performance photothermal agents in tumor theranostics through rational design and accurate control of their physiochemical properties.

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPT SS /IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPT SS /IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPT SS /IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPT SS /IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.

Regenerated silk fibroin (SF) is a type of natural biomacromolecules with outstanding biocompatibility and biodegradability. However, stimulus-responsive SF-based nanocomplex has seldom been reported for application in tumor diagnosis and therapy. Methods : As a proof-of-concept study, a multifunctional SF@MnO 2 nanoparticle-based platform was strategically synthesized using SF as a reductant and a template via a biomineralization-inspired crystallization process in an extremely facile way. Because of their mesoporous structure and abundant amino and carboxyl terminal residues, SF@MnO 2 nanoparticles were co-loaded with a photodynamic agent indocyanine green (ICG) and a chemotherapeutic drug doxorubicin (DOX) to form a SF@MnO 2 /ICG/DOX (SMID) nanocomplex. Results : The obtained product was highly reactive with endogenous hydrogen peroxide (H 2 O 2 ) in tumor microenvironment, which was decomposed into O 2 to enhance tumor-specific photodynamic therapy (PDT). Moreover, SMID nanocomplex produced a strong and stable photothermal effect upon near-infrared (NIR) irradiation for photothermal therapy (PTT) owing to the distinct photothermal response of SF@MnO 2 and stably conjugated ICG . The concurrent NIR fluorescence and magnetic resonance (MR) imaging in vivo both indicated effective tumor-specific enrichment of SMID nanoparticles via enhanced permeability and retention (EPR) effect. Animal studies further verified that SMID nanoparticles remarkably improved tumor inhibitive efficacy through combination PTT/PDT/chemotherapy with minimal systemic toxicity or adverse effect. Conclusion : This study demonstrated the promising potential of SF-based nanomaterial to address some of the key challenges in cancer therapy due to unfavorable tumor microenvironment for drug delivery., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Taking advantage of the mesoporous structure of bismuth sulfide nanostars (Bi 2 S 3 NSs), a chemotherapeutic drug of doxorubicin (DOX) and a photosensitizer of chlorin e6 (Ce6) were concurrently loaded in the PEGylated Bi 2 S 3 NSs to formulate a multifunctional nanocomplex (BPDC NSs) for tumor theranostics. BPDC NSs have excellent photothermal conversion efficiency and a capacity of yielding reactive oxygen species (ROS) upon laser irradiation, and can realize on-demand drug release by either pH-activation or thermal induction. Accumulation of the nanodrug could be monitored in real-time by infrared thermal imaging, fluorescence imaging and computed tomography (CT). More importantly, the combination effects of photothermal therapy (PTT), photodynamic therapy (PDT) and chemotherapy were demonstrated to dramatically suppress solid tumors without recurrence in vivo. Featuring low systemic toxicity and high biocompatibility, this nanoplatform could be a promising derivative of Bi 2 S 3 NSs for imaging-guided theranostics of cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy., Statement of Significance: This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.

Multifunctional nanoagents have become popular and valuable pharmaceuticals for effective cancer treatment. Moreover, there is an increasing tendency to develop therapeutic agents with excellent biocompatibility, high efficiency, specific targeting and combinatorial treatment effects. In this study, we proposed a facile technique to synthesize PEGylated (polyethylene glycol modified) magnetic Prussian blue (PB) nanoparticles with encapsulated doxorubicin (DOX), abbreviated as Fe 3 O 4 @PB/PEG/DOX NPs, for combined targeted photothermal ablation and pH-triggered chemotherapy of tumour cells. The PEGylation of Fe 3 O 4 @PB core-shell structure was achieved through a thin-film hydration process; DOX was loaded into the nanocapsule via hydrophobic interactions. An in vitro study indicated increased drug release under acidic conditions, mimicking mild acidic tumour microenvironments. Additionally, the nanocomposites exhibited superparamagnetism, contributing to an improved therapeutic effect guided by a localized magnetic field. Cytotoxicity studies demonstrated outstanding photothermal-chemotherapy combinatorial effects on HeLa cells, attributed to the targeted photothermic effect mediated by the pH-triggered cellular uptake of DOX. Specifically, the viability of HeLa cells decreased to 8.5% after treatment with the nanoagent (DOX=10μgmL -1 ) and near infrared irradiation, indicating an evident tumour inhibition effect in vitro. This study presented a nanoplatform for efficient and targeted cancer treatment, which may lead to the development of multifunctional nanodrug vehicles for cancer therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)