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[Display omitted] Combinational therapy in cancer treatment that integrates the merits of different therapies is an effective approach to improve therapeutic outcomes. Herein, a simple nanoplatform (N -CNS-CaO 2 -HA/Ce6 NCs) that synergized chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), and Ca2+ interference therapy (CIT) has been developed to combat hypoxic tumors. With high photothermal effect, excellent peroxidase-like activity, and inherent mesoporous structure, N -doped carbon nanospheres (N -CNSs) were prepared via in situ pyrolysis of an established nanoscale covalent organic frameworks (COFs) precursor. These N -CNSs acted as PTT/CDT agents and carriers for the photosensitizer chlorin e6 (Ce6), thereby yielding a minimally invasive PDT/PTT/CDT synergistic therapy. Hyaluronic acid (HA)-modified CaO 2 nanoparticles (CaO 2 -HA NPs) coated on the surface of the nanoplatform endowed the nanoplatform with O 2 /H 2 O 2 self-supply capability to respond to and modulate the tumor microenvironment (TME), which greatly facilitated the tumor-specific performance of CDT and PDT. Moreover, the reactive oxygen species (ROS) produced during PDT and CDT enhanced the Ca2+ overloading due to CaO 2 decomposition, amplifying the intracellular oxidative stress and leading to mitochondrial dysfunction. Notably, the HA molecules not only increased the cancer-targeting efficiency but also prevented CaO 2 degradation during blood circulation, providing double insurance of tumor-selective CIT. Such a nanotherapeutic system possessed boosted antitumor efficacy with minimized systemic toxicity and showed great potential for treating hypoxic tumors. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel Au NBPs@Pt NCs-ICG nanozyme was constructed with Au nanobipyrimds, Pt nanoclusters and ICG. • The Au NBPs@Pt NCs-ICG nanozyme exhibited excellent multienzymatic activity for effective TME modulation and ROS generation. • The FL/CT/PTI trimodal imaging of the nanocomposites were successfully applied. • Synergistic photothermal, photodynamic and chemodynamic cancer therapy was realized on 4T1 tumor-bearing mice model. Synergistic therapy is expected to be a promising strategy for highly effective cancer treatment. However, the rational design of a simple and multifunctional nanoplatform still remains a grand challenge. Considering the nature of weak acidic, hypoxic, and H 2 O 2 abundant tumor microenvironment, we constructed an indocyanine green (ICG) modified platinum nanoclusters (Pt NCs) decorated gold nanobipyramids (Au NBPs) to form the multifunctional nanocomposites (Au NBPs@Pt NCs-ICG) for multimodal imaging mediated phototherapy and chemodynamic cancer therapy. The photosensitizer ICG was covalently linked to Au NBPs@Pt NCs by bridging molecules of SH-PEG-NH 2 for both photodynamic therapy (PDT) and fluorescence imaging. Besides, Au NBPs@Pt NCs-ICG nanocomposites exhibited catalase- and peroxidase-like activities to generate O 2 and ·OH, which relieved the tumor hypoxia and upregulated antitumoral ROS level. Moreover, the combination of Au NBPs and ICG endowed the Au NBPs@Pt NCs-ICG with super photothermal conversion for effective photothermal imaging and therapy. In addition, the Au NBPs@Pt NCs-ICG nanoplatform displayed excellent X-ray computed tomography (CT) imaging ability due to the presence of high-Z elements (Au and Pt). Overall, our results demonstrated that Au NBPs@Pt NCs-ICG nanoplatform exhibited a multimodal imaging guided synergistic PTT/PDT/CDT therapeutic manners and held great potential as an efficient treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine‐induced anti‐tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free‐field based whole‐body ultrasound (US)‐driven nanovaccines are constructed, named G5‐CHC‐R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small‐sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia‐sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5‐CHC‐R under a free‐field based whole‐body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5‐CHC‐R triggered by US represented a superior alternative for noninvasive irradiation of deep‐seated tumors and magnification of local immune responses via driving mass release of tumor antigens and "cold‐warm‐hot" three‐state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti‐tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono‐nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology. [ABSTRACT FROM AUTHOR]

Abstract Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine‐induced anti‐tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free‐field based whole‐body ultrasound (US)‐driven nanovaccines are constructed, named G5‐CHC‐R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small‐sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia‐sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5‐CHC‐R under a free‐field based whole‐body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5‐CHC‐R triggered by US represented a superior alternative for noninvasive irradiation of deep‐seated tumors and magnification of local immune responses via driving mass release of tumor antigens and “cold‐warm‐hot” three‐state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti‐tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono‐nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.

[Display omitted] Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H+ ions, H 2 O 2 , and glutathione (GSH), the lack of O 2 , and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu2+@SA-HA core–shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H+-triggered release of Cu2+ ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes H 2 O 2 in the TME to generate O 2 to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu2+ ions could consume the excessive GSH to form Cu+ ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation. [ABSTRACT FROM AUTHOR]

The complicated tumor microenvironment (TME) is featured by low pH values, high redox status, and hypoxia, which greatly supports the genesis, development, and metastasis of tumors, leading to drug resistance and clinical failure. Moreover, a lot of immunosuppressive cells infiltrate in such TME, resulting in depressing immunotherapy. Therefore, the development of TME‐responsive nanoplatforms has shown great significance in enhancing cancer therapeutics. Metal‐phenolic networks (MPNs)‐based nanosystems, which self‐assemble via coordination of phenolic materials and metal ions, have emerged as excellent TME theranostic nanoplatforms. MPNs have unique properties including fast preparation, tunable morphologies, pH response, and biocompatibility. Besides, functionalization and surface modification can endow MPNs with specific functions for application requirements. Here, the representative engineering strategies of various polyphenols are first introduced, followed by the introduction of the engineering mechanisms of polyphenolic nanosystems, fabrication, and distinct properties of MPNs. Then, their advances in TME modulation are highlighted, such as antiangiogenesis, hypoxia relief, combination therapy sensitization, and immunosuppressive TME reversion. Finally, we will discuss the challenges and future perspectives of MPNs‐based nanosystems for enhancing cancer therapy. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease [ABSTRACT FROM AUTHOR]

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8 + cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T 1 -weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. STATEMENT OF SIGNIFICANCE: Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T 1 -weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics., 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 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Osteosarcoma (OS) is a primary malignant bone tumor that emanates from mesenchymal cells, commonly found in the epiphyseal end of long bones. The highly recurrent and metastatic nature of OS poses significant challenges to the efficacy of treatment and negatively affects patient prognosis. Currently, available clinical treatment strategies primarily focus on maximizing tumor resection and reducing localized symptoms rather than the complete eradication of malignant tumor cells to achieve ideal outcomes. The biomaterials-boosted immunotherapy for OS is characterized by high effectiveness and a favorable safety profile. This therapeutic approach manipulates the tumor microenvironments at the cellular and molecular levels to impede tumor progression. This review delves into the mechanisms underlying the treatment of OS, emphasizing biomaterials-enhanced tumor immunity. Moreover, it summarizes the immune cell phenotype and tumor microenvironment regulation, along with the ability of immune checkpoint blockade to activate the autoimmune system. Gaining a profound comprehension of biomaterials-boosted OS immunotherapy is imperative to explore more efficacious immunotherapy protocols and treatment options in this setting., (© 2024 Wiley‐VCH GmbH.)

• Tumor-reactive hybrid PLMD sensitizes hypoxic human prostate cancer cells to RT. • PLMD enhances RT-induced DNA double strand breaks and inhibits DNA repair mechanism. • PLMD reduces post-RT angiogenesis, vascular abnormality, and tumor growth. • PLMD enhances RT efficacy with prolonged mean survival by 77–93% in PCa xenografts. • PLMD+RT results in 27–40% survival of host while fractionated RT alone does not. Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT. Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT. PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate. PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NP Ce6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H 2 O 2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NP Ce6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors. [ABSTRACT FROM AUTHOR]

Various physiological characteristics of the tumor microenvironment (TME), such as hypoxia, overexpression of glutathione (GSH) and hydrogen peroxide (H 2 O 2), and mild acidity, can severely reduce the efficacy of many cancer therapies. Altering the redox balance of the TME and increasing oxidative stress can accordingly enhance the efficacy of tumor therapy. Herein, we developed a bismuth-based Cu2+-doped BiOCl nanotherapeutic platform, BCHN, able to self-supply H 2 O 2 for TME-regulated chemodynamic therapy (CDT) combined with sensitized radiotherapy (RT). BCHN released H 2 O 2 and consumed GSH to degrade the composite in the slightly acidic TME, and generated hydroxyl radicals (•OH) via a Fenton-like reaction catalyzed by copper ions, to achieve oxidative stress-enhanced CDT. The Fenton-like reaction also catalyzed H 2 O 2 to produce O 2 to relieve tumor hypoxia, and combined with the X-ray-blocking property of bismuth to realize TME-enhanced radiotherapy. Synergistic CDT/RT has previously been shown to effectively inhibit tumor cell proliferation and achieve effective tumor control. The current results demonstrated a highly efficient multifunctional bio-degradable nanoplatform for oncotherapy. Tumor microenvironment-modulated synergy of radiotherapy and chemodynamic therapy is conducive to rapid tumor ablation. Based on this principle, we fabricated a biodegradable BiOCl-based nanocomposite, BCHN. By supplying H 2 O 2 , a Fenton-like reaction generated •OH and O 2 catalyzed by copper ions, and consumed glutathione to biodegrade the composite. Overall, these actions increased tumor oxidative stress and realized the synergistic anti-tumor actions of chemodynamic therapy combined with bismuth-based sensitization radiotherapy. This strategy thus provides a unique approach to oncology therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

New biomaterials with antitumor and tissue repair function have become increasingly important for the postoperative care of melanoma surgery, which could prolong the tumor‐free survival of patients while simultaneously facilitating the reconstruction of the trauma tissue. For this purpose, a bioresorbable composite scaffold is designed which is fabricated by depositing therapeutic amorphous calcium carbonate (ACC)‐based nanoformulations in gelatin/polycaprolactone (GP) nanofibers via electrospinning. The ACC nanoformulations are integrated with Fe2+‐preactivated bleomycin to deliver biocatalytically enhanced therapeutic effect while the hydrolysable ACC contents can act as proton scavengers to ameliorate the tumor tissue acidity in situ, leading to sustained inhibition on tumor recurrence and metastasis. The acid‐triggered ACC decomposition also releases Ca2+ to activate the downstream Wnt/β‐catenin signaling pathways, which can cooperate with the healing effect of the GP substrate and accelerate wound regeneration. The nanoengineered scaffold can be useful as a supplementary treatment for the postoperative management of melanoma. [ABSTRACT FROM AUTHOR]

Modulating the hostile tumor microenvironment (TME) rather than directly killing cancer cells may be an effective strategy to improve the therapeutic benefits in cancer treatment. Herein, FeWOX nanosheets are constructed as cascade bioreactors to modulate the TME and enhance radiotherapy and immunotherapy of tumors. Synthesized by the thermal‐decomposition method and modified by poly(ethylene glycol) (PEG), the obtained FeWOX‐PEG with multivalent metal elements (Fe2+/3+, W5+/6+) exhibit efficient catalytic decomposition of hydrogen peroxide (H2O2) to generate hydroxyl radicals (•OH) for chemo‐dynamic therapy (CDT). The generated high valence of metal ions (Fe3+/W6+) in FeWOX‐PEG are reduced by endogenous glutathione (GSH), both leading to depletion of GSH and further amplified oxidative stress, and resulting in the reduced metal valence statuses (Fe2+/W5+) enabling cascade bioreactions. Such FeWOX‐PEG bioreactors enhance the oxidative stress in the tumor and interact with X‐rays, significantly improving cancer radiotherapy (RT). Furthermore, the reactive oxygen species (ROS)‐induced inflammation caused by FeWOX‐PEG in TME activates the immune system and promotes the tumor‐infiltration of various types of immune cells, which working together with cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) checkpoint blockade could elicits a robust immune response to defeat tumors. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy strategies leveraging the body’s own immune system against cancer cells have gained significant attention due to their remarkable therapeutic efficacy. Several immune therapies have been approved for clinical use while expanding the modalities of cancer therapy. However, they are still not effective in a broad range of cancer patients because of the typical immunosuppressive microenvironment and limited antitumor immunity achieved with the current treatment. Novel approaches, such as nanoparticle-mediated cancer immunotherapies, are being developed to overcome these challenges. Various types of nanoparticles, including liposomal, polymeric, and metallic nanoparticles, are reported for the development of effective cancer therapeutics. Metallic nanoparticles (MNPs) are one of the promising candidates for anticancer therapy due to their unique theranostic properties and are thus explored as both imaging and therapeutic agents. In addition, MNPs offer a dense surface functionalization to target tumor tissue and deliver genetic, therapeutic, and immunomodulatory agents. Furthermore, MNPs interact with the tumor microenvironment (TME) and regulate the levels of tumor hypoxia, glutathione (GSH), and reactive oxygen species (ROS) for remodulation of TME for successful therapy. In this review, we discuss the role of nanoparticles in tumor microenvironment modulation and anticancer therapy. In particular, we evaluated the response of MNP-mediated immune cells, such as dendritic cells, macrophages, T cells and NK cells, against tumor cells and analyzed the role of MNP-based cancer therapies in regulating the immunosuppressive environment.

• Nanoparticle-based artificial antigen presenting cells (aAPCs) can directly activate functional T cells in lymph node. • Cancer nanovaccines are capable of indirectly inducing T cell activation by stimulating antigen presenting cells (APCs). • Tumor microenvironment (TME) modulation by downregulating immunosuppressive signals can reinvigorate T cell activity. • Combination therapy using nanosystems can elicit a strong T cell response. Immunotherapy (e.g. , checkpoint blockade, adoptive T cell therapy, cancer vaccine) has emerged as one of the most important treatment modalities for cancer in the past two decades. While these approaches are promising, the response rates observed in clinical trials are less than 30% due to tumor heterogeneity and complexity of the tumor microenvironment. Smart nanosystems have the potential to address some of the limitations associated with immunotherapy. Herein, we review applications of nanosystem-mediated immunotherapy for functional T cell activation, including formation of artificial antigen presenting cells, cancer nanovaccination, tumor microenvironment modulation, and combination therapy. Finally, we propose areas of research for the future development of nanosystem-mediated cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abnormal tumor vasculature is reported to severely hinder the therapeutic potency of diverse cancer therapeutics by restricting their intratumoral accumulation and/or causing therapeutic resistance. Herein, a microbubble-assisted ultrasonication technology (MAUT) of systemic administration of octafluoropropane-filled microbubbles together with tumor localized ultrasound (US) exposure is developed to generally promote intratumoral accumulation efficacy of three kinds of anti-tumor drugs with varying sizes through the cavitation effect-induced disruption of tumor blood vessels. MAUT was further shown to enable selective tumor hypoxia attenuation by filling microbubbles with high-purity oxygen and thus reducing the production of immunosuppressive lactic acids by suppressing glycolysis in cancer cells. Resultantly, MAUT markedly enhanced the therapeutic outcome of systemically administered anti-programmed death-1 (anti -PD-1) and chemotherapeutic doxorubicin (DOX) with and without using nanoscale liposomes as delivery vehicles. This work highlights that MAUT is a biocompatible yet versatile strategy to effectively reinforce the therapeutic potency of a broad range of cancer therapeutics, promising for future clinical usage. [ABSTRACT FROM AUTHOR]

A hollow mesoporous manganese dioxide-based (H-MnO 2) multifunctional nanoplatform, H-MnO 2 @AFIPB@PDA@Ru-NO@FA (MAPRF NPs), was prepared for synergistic cancer treatment, in which a histone deacetylase inhibitor AFIPB was loaded in its hollow cavity and a ruthenium nitrosyl donor (Ru-NO) and a folic acid (FA) targeting group were covalently decorated on its covered polydopamine (PDA) layer. The MAPRF NPs showed tumor microenvironment (TME)-responsive properties of depletion of glutathione (GSH) to disrupt the antioxidant defense system and on-demand drug delivery. And the released Mn2+ further catalyzed the decomposition of endogenous H 2 O 2 to produce highly toxic hydroxyl radicals (·OH) for enhanced chemodynamic therapy (CDT). Furthermore, upon 808 nm light irradiation MAPRF NPs exhibited controlled nitric oxide (NO) delivery and simultaneously produced significant photothermal effect. Consequently, MAPRF NPs showed high mortality toward cancer cells in the presence of 808 nm light irradiation. This work provides a paradigm of multimodal synergistic therapy that combines NO-based gas therapy with TME modulation for efficient antitumor therapy. A novel mesoporous MnO 2 -based multifunctional nanoplatform exhibited near-infrared light-controlled nitric oxide delivery, tumor microenvironment (TME)-responsive release of a histone deacetylase inhibitor and TME modulation for efficient multimodal synergistic antitumor therapy. [Display omitted] • A hollow mesoporous MnO 2 -based multifunctional NO-releasing nanoplatform was prepared. • Tumor microenvironment-responsive of GSH depletion and hydroxyl radical production. • Controlled NO delivery and photothermal effect was achieved upon 808 nm light irradiation. • It showed high mortality toward cancer cells under 808 nm light irradiation. • Synergistic multimodal therapies were attributed to the enhanced antitumor efficiency. [ABSTRACT FROM AUTHOR]

The complicated tumor microenvironment (TME) is featured by low pH values, high redox status, and hypoxia, which greatly supports the genesis, development, and metastasis of tumors, leading to drug resistance and clinical failure. Moreover, a lot of immunosuppressive cells infiltrate in such TME, resulting in depressing immunotherapy. Therefore, the development of TME-responsive nanoplatforms has shown great significance in enhancing cancer therapeutics. Metal-phenolic networks (MPNs)-based nanosystems, which self-assemble via coordination of phenolic materials and metal ions, have emerged as excellent TME theranostic nanoplatforms. MPNs have unique properties including fast preparation, tunable morphologies, pH response, and biocompatibility. Besides, functionalization and surface modification can endow MPNs with specific functions for application requirements. Here, the representative engineering strategies of various polyphenols are first introduced, followed by the introduction of the engineering mechanisms of polyphenolic nanosystems, fabrication, and distinct properties of MPNs. Then, their advances in TME modulation are highlighted, such as antiangiogenesis, hypoxia relief, combination therapy sensitization, and immunosuppressive TME reversion. Finally, we will discuss the challenges and future perspectives of MPNs-based nanosystems for enhancing cancer therapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2022 Wiley Periodicals LLC.)

Chemodynamic therapy (CDT), which takes advantages of CDT agents to selectively induce tumor cells apoptosis via Fenton or Fenton-like reactions, is considered to have great potential for tumor-specific treatment. However, the therapeutic outcome of CDT still faces the challenges of the lack of efficient CDT agents and insufficient supply of endogenous H 2 O 2. Herein, to explore highly efficient CDT agents as well as increase the H 2 O 2 content at tumor sites to enhance the efficiency of CDT, a red blood cell (RBC) membrane encapsulated Nb 2 C quantum dots/lactate oxidase (LOD) nanocatalyst (Nb 2 C QDs/LOD@RBC) was proposed. Nb 2 C quantum dots are quite prospective as efficient CDT agents in CDT application due to the intrinsic merits such as abundant active catalytic sites, satisfactory hydrophilicity, and good biocompatibility. The encapsulation of Nb 2 C QDs and LOD into RBC membrane was to prolong the in vivo circulation time of the nanocatalyst and increase its tumor sites accumulation. The accumulated Nb 2 C QDs/LOD@RBC nanocatalyst could efficiently convert the endogenous H 2 O 2 into ·OH, while the overexpressed lactate could be catalyzed into H 2 O 2 by LOD to replenish the depletion of H 2 O 2. The cascaded reaction between Nb 2 C quantum dots and LOD eventually enhanced the CDT effect of Nb 2 C QDs/LOD@RBC nanocatalyst for tumors growth inhibition. Moreover, the consumption of lactate at tumor sites induced by Nb 2 C QDs/LOD@RBC nanocatalyst leads to the increased infiltration of antitumoral M1 tumor-associated macrophages, which alleviated the immunosuppression of the tumor microenvironment and further maximized the therapeutic outcome of CDT. Taken together, the Nb 2 C QDs/LOD@RBC nanocatalyst provides a promising paradigm for tumor inhibition via catalytic cascaded reaction between Nb 2 C quantum dots and LOD. [Display omitted] • The Nb 2 C QDs/LOD@RBC nanocatalyst has been developed for enhanced CDT. • Enhanced CDT is attribute to the cascaded reaction between Nb 2 C QDs and LOD. • The nanocatalyst consumes lactate to increase the infiltration of M1 macrophages. [ABSTRACT FROM AUTHOR]

Rationale: Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Methods: Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist ( D PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core ( D PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. Results: D PPA-TRPP/Tab reassembled into a micellar structure in vivo with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by D PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. In vivo results indicated that D PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. Conclusion: The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The specific characteristics of the tumor microenvironment (TME) and monotherapy always lead to poor therapy effects for tumors. Hereby, we have developed a smart multifunctional theranostic agent-SSMID (Se@SiO 2 @MnO 2 -ICG/DOX) nanocomposites (NCs) that could intelligently respond to the TME for enhanced chemotherapy/photothermal/chemodynamic therapy guided by magnetic resonance imaging (MRI). The SSMID NCs were composed of indocyanine green (ICG) and doxorubicin hydrochloride (DOX) co-loaded porous Se@SiO 2 @MnO 2. Under the specific conditions of the TME (slightly acidic, H 2 O 2 and GSH overexpression), the MnO 2 NPs were specifically decomposed and then SSMID released Mn2+, DOX and Se, which played roles in chemodynamic therapy (CDT), chemotherapy, protecting normal tissues and inhibiting tumor cells by modulating reactive oxygen species (ROS), respectively. MnO 2 reacted with glutathione (GSH) and H 2 O 2 to generate O 2 and Mn2+, which alleviated tumor hypoxia to improve chemotherapy and depleted GSH to enhance oxidative stress for chemodynamic therapy. More importantly, SSMID NCs could simultaneously exert the photothermal therapy (PTT) effect with near-infrared laser irradiation and promote the release of Mn2+ and DOX to achieve enhanced chemotherapy/chemodynamic therapy. In addition, the released Mn2+ could be used as a T1-weighted MRI contrast agent to monitor tumor location. The SSMID NCs exhibited a pronounced tumor growth inhibitory effect and promising biological safety, which develop a new method to rationally design nano-theranostic agents with enhanced performance for anti-tumor. [Display omitted] • The multifunctional SSMID was fabricated for MRI guided enhanced PTT/CDT/chemotherapy. • The smart theranostic agent-SSMID that could intelligently respond to the TME. • The released Se could protect normal tissues and inhibit tumor cells. • MnO 2 alleviated tumor hypoxia to improve chemotherapy and deplete GSH to enhance oxidative stress for CDT. [ABSTRACT FROM AUTHOR]

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases. [ABSTRACT FROM AUTHOR]

Globally, a rising burden of complex diseases takes a heavy toll on human lives and poses substantial clinical and economic challenges. This review covers nanomedicine and nanotechnology-enabled advanced drug delivery systems (DDS) designed to address various unmet medical needs. Key nanomedicine and DDSs, currently employed in the clinic to tackle some of these diseases, are discussed focusing on their versatility in diagnostics, anticancer therapy, and diabetes management. First-hand experiences from our own laboratory and the work of others are presented to provide insights into strategies to design and optimize nanomedicine- and nanotechnology-enabled DDS for enhancing therapeutic outcomes. Computational analysis is also briefly reviewed as a technology for rational design of controlled release DDS. Further explorations of DDS have illuminated the interplay of physiological barriers and their impact on DDS. It is demonstrated how such delivery systems can overcome these barriers for enhanced therapeutic efficacy and how new perspectives of next-generation DDS can be applied clinically.

Cancer immunotherapy strategies leveraging the body's own immune system against cancer cells have gained significant attention due to their remarkable therapeutic efficacy. Several immune therapies have been approved for clinical use while expanding the modalities of cancer therapy. However, they are still not effective in a broad range of cancer patients because of the typical immunosuppressive microenvironment and limited antitumor immunity achieved with the current treatment. Novel approaches, such as nanoparticle-mediated cancer immunotherapies, are being developed to overcome these challenges. Various types of nanoparticles, including liposomal, polymeric, and metallic nanoparticles, are reported for the development of effective cancer therapeutics. Metallic nanoparticles (MNPs) are one of the promising candidates for anticancer therapy due to their unique theranostic properties and are thus explored as both imaging and therapeutic agents. In addition, MNPs offer a dense surface functionalization to target tumor tissue and deliver genetic, therapeutic, and immunomodulatory agents. Furthermore, MNPs interact with the tumor microenvironment (TME) and regulate the levels of tumor hypoxia, glutathione (GSH), and reactive oxygen species (ROS) for remodulation of TME for successful therapy. In this review, we discuss the role of nanoparticles in tumor microenvironment modulation and anticancer therapy. In particular, we evaluated the response of MNP-mediated immune cells, such as dendritic cells, macrophages, T cells and NK cells, against tumor cells and analyzed the role of MNP-based cancer therapies in regulating the immunosuppressive environment. [ABSTRACT FROM AUTHOR]

Solid tumors possess a unique internal environment with high-level thiols (mainly glutathione), over-expressed H 2 O 2 , and low oxygen partial pressure, which severely restrict the radiotherapy (RT) efficacy. To overcome the imperfections of RT alone, there is vital to design a multifunctional radiosensitizer that simultaneously achieves multimodal therapy and tumor microenvironment (TME) regulation. Bismuth (Bi)-based nanospheres are wrapped in the MnO 2 layer to form core-shell-structured radiosensitizer (Bi@Mn) that can effectively load docetaxel (DTX). The solubility of Bi@Mn-DTX is further improved via folic acid-modified amphiphilic polyethylene glycol (PFA). Bi@Mn-DTX-PFA can specifically respond to the TME to realize multimodal therapy. Primarily, the outer MnO 2 layer responds with H 2 O 2 and glutathione to release oxygen and generate •OH, thereby alleviating hypoxia and achieving chemodynamic therapy (CDT). Afterward, the strong coordination between Bi 3+ and deprotonated thiol groups in glutathione allows the mesoporous Bi-containing core bonding with glutathione to form a water-soluble complex. These actions conduce Bi@Mn-DTX-PFA degradation, further releasing DTX to implement chemotherapy (CHT). In addition, the degradation in vivo and tumor enrichment of Bi@Mn-PFA are explored via T 1 -weighted magnetic resonance and computed tomography imaging. The biodegradable composite Bi@Mn-DTX-PFA can simultaneously modulate the TME and achieve multimodal treatment (RT/CDT/CHT) for hypoxic tumors., (© 2021 Wiley-VCH GmbH.)

Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients., (© 2021 IOP Publishing Ltd.)

Solid tumors inevitably develop radioresistance due to low oxygen partial pressure in the tumor microenvironment. Despite numerous attempts, there are still few effective ways to avoid the hypoxia-induced poor radiotherapeutic effect. To overcome this problem, platinum (Pt) nanodots were fabricated into a mesoporous bismuth (Bi)-based nanomaterial to construct a biodegradable nanocomposite BiPt-folic acid-modified amphiphilic polyethylene glycol (PFA). BiPt-PFA could act as a radiosensitizer to enhance the absorption of X-rays at the tumor site and simultaneously trigger response behaviors related to the tumor microenvironment due to the enrichment of materials in the tumor area. During this process, the Bi-based component consumed glutathione via coordination, thus altering the oxidative stress balance, while Pt nanoparticles catalyzed the decomposition of hydrogen peroxide to generate oxygen, thereby relieving tumor hypoxia. Both Pt and Bi thus co-modulated the tumor microenvironment to improve the radiotherapeutic effect. In addition, Pt dots in BiPt-PFA had strong near-infrared absorption ability and created an intensive photothermal therapeutic effect. Modulation of the tumor microenvironment could thus improve the therapeutic effect in hypoxic tumors by a combination of photothermal therapy and enhanced radiotherapy. BiPt-PFA, as a biodegradable nanocomposite, may thus modulate the tumor microenvironment to enhance the hypoxic tumor therapeutic effect by thermoradiotherapy.

Combination therapy that could better balance immune activation and suppressive signals holds great potential in cancer immunotherapy. Herein, we serendipitously found that the pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol- b -cationic polypeptide can not only serve as a nanocarrier but also cause immunogenic cell death (ICD) through preapoptotic exposure of calreticulin. After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model. Treatment efficacy attributes to three key factors: (i) singlet oxygen generation by HPPH-mediated photodynamic therapy (PDT); (ii) increased dendritic cell (DC) recruitment and immune response provocation after ICD induced by pRNVs and PDT; and (iii) tumor microenvironment modulation by IND via enhancing P-S6K phosphorylation for CD8 + T cell development. This study exploited the nanocarrier to induce ICD for the host's immunity activation. The "all-in-one" smart nanovesicles allow the design of multifunctional materials to strengthen cancer immunotherapy efficacy.

Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.