Acidic Tumor Microenvironment Research Articles

Dendrimer/metal-phenolic nanocomplexes encapsulating CuO2 for targeted magnetic resonance imaging and enhanced ferroptosis/cuproptosis/chemodynamic therapy by regulating the tumor microenvironment

The combination of ferroptosis, cuproptosis, and chemodynamic therapy (CDT) would be a potential strategy for tumor diagnosis and enhanced treatment. However, the therapeutic effect was severely limited by the lack of specific delivery of catalytic ions and the low Fenton reaction efficiency in tumor microenvironment (TME) with excess glutathione, limited acidity and insufficient endogenous hydrogen peroxide. In this work, p-carboxybenzenesulfonamide (BS), a carbonic anhydrase IX (CA IX) inhibitor, was modified on the surface of generation-5 poly(amidoamine) dendrimer to load copper peroxide nanoparticles, which were complexed with iron (Fe)-tannic acid (TF) networks for targeted magnetic resonance (MR) imaging and enhanced ferroptosis/cuproptosis/CDT by regulating TME. The formed CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm could be specifically accumulated at tumor site and effectively internalized by metastatic 4T1 cells via the specific interaction between BS and CA IX over-expressed on tumor cells. Meanwhile, the inhibition of CA IX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity in TME. Moreover, the reduction of Fe3+/Cu2+ by intracellular glutathione (GSH) could further amplify ROS generation and enhance CDT efficacy, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy. In vivo experimental results demonstrated that CuO2@G5-BS/TF could provide better tumor MR imaging, effectively inhibit the growth and metastasis of 4T1 breast tumors, and be metabolized without significant systemic toxicity. Thus, CuO2@G5-BS/TF nanocomplexes provided a new approach for targeted MR imaging and enhanced ferroptosis/cuproptosis/CDT of triple-negative breast cancer. Statement of significanceTaking the advantage of dendrimer and metal-phenolic system, stable CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm were synthesized to efficiently load Fe3+ and CuO2 nanoparticles for TNBC treatment and MR imaging. CuO2@G5-BS/TF nanocomplexes could target tumor cells overexpressing CAIX via the specific binding with BS, and the inhibition of CAIX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity. The reduction of Fe3+/Cu2+ by intracellular GSH could further amplify ·OH generation, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy by enhanced ferroptosis/cuproptosis/CDT via tumor microenvironment regulation.

H2O2 self-supplying Ce6@ZIF-8/PDA/CuO2/HA (CZPCH) nanoplatform for enhanced reactive oxygen species (ROS)-mediated tumor therapy

Tumor hypoxia, limited H2O2 levels, and abundant glutathione (GSH) in the tumor microenvironment (TME) pose challenges for high-efficiency reactive oxygen species (ROS)-mediated therapies. To address these limitations, an intelligent ROS-mediated nanoplatform, Ce6@ZIF-8/PDA/CuO2/HA (CZPCH), with photodynamic activity, self-supplied H2O2, Fenton-like reaction, GSH-depletion and photothermal activity was designed for efficient tumor treatment. In the acidic TME, CuO2 in CZPCH deposits into Cu2+ and H2O2, consuming GSH and triggering Fenton-like reactions to generate hydroxyl radical (•OH), enabling efficient chemodynamic therapy (CDT). Moreover, the presence of Ce6 and PDA enables CZPCH to exhibit excellent singlet oxygen (1O2) and temperature increase performance 660 nm and 808 nm laser irradiation, respectively, resulting in efficient photodynamic therapy (PDT) and photothermal therapy (PTT) efficacy. Interestingly, the temperature increase from PTT significantly enhances •OH and 1O2 generation, achieving high-efficiency ROS-based therapeutic efficacy. This synergistic CDT/PDT/PTT treatment demonstrates excellent anti-tumor efficacy and illuminates novel ROS-based therapeutic strategy design.

MOF-derived cobalt-iron containing nanocomposite with cascade-catalytic activities for multimodal synergistic tumor therapy

Reactive oxygen species (ROS)-driven chemodynamic therapy has emerged as a promising anti-tumor strategy. However, the insufficient hydrogen peroxide (H2O2) supply in tumor microenvironment results in a low Fenton reaction rate and subsequently poor ROS production and therapeutic efficacy. Herein, we report on a new nanocomposite MIL-53@ZIF-67/S loaded with doxorubicin and glucose oxidase, which is decomposed under the acidic tumor microenvironment to release Fe3+, Co3+, glucose oxidase, and doxorubicin. The released content leads to synergistic anti-tumor effect through the following manners: 1) doxorubicin is directly used for chemotherapy; 2) Fe3+and Co3+ result in glutathione depletion and Fenton reaction activation through Fe2+ and Co2+ generation to achieve chemodynamic therapy; 3) glucose oxidase continuously catalyzes glucose consumption to induce starvation of the cancer cells, and 4) at the same time the produced gluconic acid and H2O2 significantly promote Fenton reaction and further boost chemodynamic therapy. This work not only demonstrates the high anti-tumor effect of the new nanocomposite, but also provides an innovative strategy for the development of a multi-in-one nanoplatform for cancer therapy.

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

Nanozyme-catalyzed oxygen self-supplying mitochondria-targeting nanoplatform for precise photodynamic therapy

Local hypoxia in tumors poses significant challenges to the effectiveness of oxygen-dependent photodynamic therapy (PDT). Herein, a versatile mitochondrial targeting and pH-responsive nanozyme platform (noted as Mito CPs-p) is developed for solving local hypoxia in tumors and enhancing the PDT efficiency. Mito CPs-p, which consists of carbon-dot-supported atomically dispersed platinum (CPs) with further surface modifications of triphenylphosphine (PPh3) and pH-responsive porphyrin polymers. The PDT of Mito CPs-p was activated in acidic tumor microenvironment and exposed platinum for catalyzing endogenous H2O2 decomposition to produce O2 at tumor sites, due to the hydrophobic-hydrophilic transition of pH-responsive porphyrin-containing polymers in Mito CPs-p from hydrophobic to hydrophilic, which can markedly enhance PDT efficiency. Besides, the rational integration of mitochondria-targeting will improve the bioavailability of reactive oxygen species and further strengthen the PDT efficiency. In vitro results indicated that Mito CPs-p has exhibited excellent mitochondrial targeting capability and the ROS yield of Mito CPs-p was dramatically amplified. In vivo data further revealed that the Mito CPs-p displayed superb therapeutic efficacy. Hence, the Mito CPs-p provides new insights for efficient PDT in hypoxia solid tumors.

GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy

BackgroundSeveral PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies.ResultsTo overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the “FG loop” of hPD-1, distinct from those of Keytruda® (“C’D loop”) and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201’s binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME.ConclusionsIn summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

Integrated drug delivery system loading ROS-generating antitumor drugs for signal-amplified photoacoustic imaging and multimodal tumor therapy

The usefulness of antitumor drugs that produce reactive oxygen species (ROS) in accurate tumor diagnosis and treatment has been underestimated. Here, β-Lapachone (Lapa, antitumor drugs), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS, precursor photoacoustic agents) and 2, 2′-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH, free radical initiators) were successfully loaded into zeolitic imidazolate framework (ZIF) in situ by a one-pot method and named Lapa/ABTS/AIPH@ZIF-67 nanoparticles (LBIZ NPs). After entering the tumor cell, the ZIF structure of LBIZ NPs is disrupted in the acidic tumor microenvironment, which results in the release of Co2+ and drugs. In one hand, Lapa and Co2+ together increased hydroxyl radicals (•OH) levels to achieve Enhanced-Chemodynamic therapy (ECDT). As the amount of •OH went up, the amount of ABTS•+, the oxidation product of ABTS, would also increase, thus increasing the sensitivity and contrast of photoacoustic imaging. In the other hand, the photothermal effect produced by ABTS•+ induces AIPH to crack and release alkyl radicals (•R) to achieve thermodynamic therapy. The LBIZ NPs achieved more effective tumor treatments by fully utilizing light and heat energy. Hence, this integrated drug delivery system is able to achieve signal-amplified photoacoustic imaging and Enhanced-Chemodynamic/Photothermal/Thermodynamic trimodal combination therapy. This work provides a new insight into the application of ROS-generating antitumor drugs to precise imaging of tumors.

Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors

The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors.

Long-term combined blockade of CXCR4 and PD-L1 with in vivo reassembly for intensive tumor interference

Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings.

Amorphous CaCO3-bioreactor for tumor microenvironment regulation to reinforce tumor chemoimmunotherapy

Developing efficient nanomedicines to modulate the immunosuppressive tumor microenvironment (TME) is a highly sought-after method for improving the adverse clinical outcomes of immunotherapy. In this study, we designed a novel tumor immune stimulatory nanomedicine to regulate the immunosuppressive TME in multiple directions. This nanomedicine is liposome-modified amorphous calcium carbonate (ACC) nanoparticles (referred to as CEL/ACC-LP NPs) loaded with chemotherapeutic medication celastrol (CEL). CEL/ACC-LP NPs explosively release calcium ions (Ca2+) and CEL in the tumor acidic microenvironment, and rapidly deplete H+ to alleviate the tumor acidic microenvironment, exhibiting intrinsic immune regulatory activity in synergistic tumor chemoimmunotherapy. CEL induces reactive oxygen species (ROS) to promote Ca2+ influx, exacerbating cellular Ca2+ overload. In addition, CEL/ACC-LP NPs can cause unique immunogenic cell death (ICD) effects. Therefore, the multi-directional regulation of tumor cells through simple nano preparation will offer a potent approach to improve the efficacy of chemoimmunotherapy.

Acid-Triggered Degradation of Three-In-One Ag2S Quantum Dots for In Situ Ratiometric NIR-II Fluorescence Imaging-Guided Ion/Gas Combination Therapy.

Smart theranostic nanoprobes with the integration of multiple therapeutic modalities are preferred for precise diagnosis and efficient therapy of tumors. However, it remains a big challenge to arrange the imaging and two or more kinds of therapeutic agents without weakening the intended performances. In addition, most existing fluorescence (FL) imaging agents suffer from low spatiotemporal resolution due to the short emission wavelength (<900 nm). Here, novel three-in-one Ag2S quantum dot (QD)-based smart theranostic nanoprobes were proposed for in situ ratiometric NIR-II FL imaging-guided ion/gas combination therapy of tumors. Under the acidic tumor microenvironment, three-in-one Ag2S QDs underwent destructive degradation, generating toxic Ag+ and H2S. Meanwhile, their FL emission at 1270 nm was weakened. Upon introduction of a downconversion nanoparticle (DCNP) as the delivery carrier and NIR-II FL reference signal unit, the formed Ag2S QD-based theranostic nanoprobes could achieve precise diagnosis of tumors through ratiometric NIR-II FL signals. Also, the generated Ag+ and H2S enabled specific ion/gas combination therapy toward tumors. By combining the imaging and therapeutic functions, three-in-one Ag2S QDs may open a simple yet reliable avenue to design theranostic nanoprobes.

Multimodal Imaging-Guided Synergistic Photodynamic Therapy Using Carbonized Zn/Co Metal-Organic Framework Loaded with Cytotoxin Against Liver Cancer.

The study aimed to address the non-specific toxicity of cytotoxins (CTX) in liver cancer treatment and explore their combined application with the photosensitizer Ce6, co-loaded into carbonized Zn/Co bimetallic organic frameworks. The goal was to achieve controlled CTX release and synergistic photodynamic therapy, with a focus on evaluating anti-tumor activity against human liver cancer cell lines (Hep G2). Purified cobra cytotoxin (CTX) and photosensitizer Ce6 were co-loaded into carbonized Zn/Co bimetallic organic frameworks, resulting in RGD-PDA@C-ZIF@(CTX+Ce6). The formulation was designed with surface-functionalization using polydopamine and tumor-penetrating peptide RGD. This approach aimed to facilitate controlled CTX release and enhance the synergistic effect of photodynamic therapy. The accumulation of RGD-PDA@C-ZIF@(CTX+Ce6) at tumor sites was achieved through RGD's active targeting and the enhanced permeability and retention (EPR) effect. In the acidic tumor microenvironment, the porous structure of the metal-organic framework disintegrated, releasing CTX and Ce6 into tumor cells. Experiments demonstrated that RGD-PDA@C-ZIF@(CTX+Ce6) nanoparticles, combined with near-infrared laser irradiation, exhibited optimal anti-tumor effects against human liver cancer cells. The formulation showcased heightened anti-tumor activity without discernible systemic toxicity. The study underscores the potential of utilizing metal-organic frameworks as an efficient nanoplatform for co-loading cytotoxins and photodynamic therapy in liver cancer treatment. The developed formulation, RGD-PDA@C-ZIF@(CTX+Ce6), offers a promising avenue for advancing the clinical application of cytotoxins in oncology, providing a solid theoretical foundation for future research and development.

Acid-Activated TAT Peptide-Modified Biomimetic Boron Nitride Nanoparticles for Enhanced Targeted Codelivery of Doxorubicin and Indocyanine Green: A Synergistic Cancer Photothermal and Chemotherapeutic Approach.

The evolution of nano-drug delivery systems addresses the limitations of conventional cancer treatments with stimulus-responsive nanomaterial-based delivery systems presenting temporal and spatial advantages. Among various nanomaterials, boron nitride nanoparticles (BNNs) demonstrate significant potential in drug delivery and cancer treatment, providing a high drug loading capacity, multifunctionality, and low toxicity. However, the challenge lies in augmenting nanomaterial accumulation exclusively within tumors while preserving healthy tissues. To address this, we introduce a novel approach involving cancer cell membrane-functionalized BNNs (CM-BIDdT) for the codelivery of doxorubicin (Dox) and indocyanine green to treat homologous tumor. The cancer cell membrane biomimetic CM-BIDdT nanoparticles possess highly efficient homologous targeting capabilities toward tumor cells. The surface modification with acylated TAT peptides (dTAT) further enhances the nanoparticle intracellular accumulation. Consequently, CM-BIDdT nanoparticles, responsive to the acidic tumor microenvironment, hydrolyze amide bonds, activate the transmembrane penetrating function, and achieve precise targeting with substantial accumulation at the tumor site. Additionally, the photothermal effect of CM-BIDdT under laser irradiation not only kills cells through thermal ablation but also destroys the membrane on the surface of the nanoparticles, facilitating Dox release. Therefore, the fabricated CM-BIDdT nanoparticles orchestrate chemo-photothermal combination therapy and effectively inhibit tumor growth with minimal adverse effects, holding promise as a new modality for synergistic cancer treatment.

Fast tumor imaging using pH-responsive aggregation of cyanine dyes with rapid clearance

Rapid and selective tumor detection using conventional pH-activatable chemical probes as contrast agents is challenging. Moreover, a large proportion of the contrast agent is usually retained in the body long-term, which causes potential toxicity risks. In this study, we developed a fluorescent sensor, CypH2S, with a pH-sensitive cyclic substructure for detection of acidic tumor microenvironment. Upon pH variation, the sensor underwent structural changes: the closed-ring form, CypH2S-C, exhibited suppressed dye aggregation, while the open-ring form, CypH2S-O, tended to aggregate in aqueous solutions under slightly acidic conditions. Importantly, CypH2S facilitated rapid and selective tumor visualization in a living mouse model via fluorescence imaging of its pH-responsive aggregation with a 1.9-fold tumor/background ratio (< 1 h). Furthermore, prompt clearance of CypH2S from the bloodstream post-tumor detection occurred because of the relatively small size of the aggregates and cell impermeability. These properties would make CypH2S a promising candidate for clinical tumor diagnosis.

Mesoporous Organosilica-Platinum Janus nanomotor coordinated by charge reversal for deep tumor penetration and promoted chemotherapy

Enhancing the diffusion capability of nanoparticles through rational engineering is an effective strategy for promoting the penetration of nanotherapeutic systems into tumors. However, the efficiency of diffusion remains inadequate due to the unchanged passive diffusion mode. Nanomotors hold promise for achieving deep tumor permeability due to their self-propelled motility. Developing smart-responsive nanomotor therapeutic systems for long circulation, deep tumor penetration, and well-timed drug release presents significant challenges. Herein, we design and synthesize a kind of nanomotor with charge reversal capability that shifts from negative to positive charge in response to weakly acidic tumor microenvironment on the base of the Janus nanostructure, which consists of the mesoporous organosilica degraded in response to glutathione and asymmetric Pt provided driving force by catalyzing endogenous H2O2 to decompose into O2. The cap-like Janus structure is prepared by a facile adsorption − reduction method. Such a nanomotor can achieve deep tumor penetration by the synergism of charge reversal and self-propelled motion. The drug-loaded nanomotor displays a superior tumor killing effect, which provides a promising strategy for the nano-chemotherapy system with deep penetration ability to break through the limitation of current tumor treatment.

Core-shell nanomedicine based on multifunctional tetrahedral DNA nanostructures for synergistic enhancement of tumor chemodynamic/chemo-immunotherapy

Immune checkpoint blockade therapy has made great strides in cancer treatment, but conventional immune checkpoint blockade antibodies often lead to overactivation of the immune system and severe immune-related adverse effects. Herein, we report the design of a nanomedicine (denoted as CPD@M−TDN) based on multifunctional tetrahedral DNA nanostructures (M−TDN). In this system, a bimetallic metal–organic framework (Cu/ZIF-8) is synthesized as the core; doxorubicin-loaded polydopamine acts as a shell to reduce the immunogenicity of the nanomaterials in peripheral blood. Finally, the CpG oligodeoxynucleotides and PD-L1 aptamer-based M−TDN are coupled to the core–shell structure nanomedicine through the biotin-avidin-system. Under the acidic tumor microenvironment, the decomposition of Cu/ZIF-8 and the release of copper ions and doxorubicin can lead to immunogenic death of tumor cells through chemodynamic/chemotherapy. Furthermore, the M−TDN has the dual effects of weakening the immunosuppressive microenvironment with PD-L1 aptamer and promoting dendritic cell activation with the immunostimulant CpG. Overall, the developed CPD@M−TDN can effectively enhance the response rate to immunotherapy and has excellent potential in the field of integrated tumor treatment.

Targeted pH-Activated Peptide-Based Nanomaterials for Combined Photodynamic Therapy with Immunotherapy.

Photodynamic therapy (PDT) has demonstrated efficacy in eliminating local tumors, yet its effectiveness against metastasis is constrained. While immunotherapy has exhibited promise in a clinical context, its capacity to elicit significant systemic antitumor responses across diverse cancers is often limited by the insufficient activation of the host immune system. Consequently, the combination of PDT and immunotherapy has garnered considerable attention. In this study, we developed pH-responsive porphyrin-peptide nanosheets with tumor-targeting capabilities (PRGD) that were loaded with the IDO inhibitor NLG919 for a dual application involving PDT and immunotherapy (PRGD/NLG919). In vitro experiments revealed the heightened cellular uptake of PRGD/NLG919 nanosheets in tumor cells overexpressing αvβ3 integrins. The pH-responsive PRGD/NLG919 nanosheets demonstrated remarkable singlet oxygen generation and photocytotoxicity in HeLa cells in an acidic tumor microenvironment. When treating HeLa cells with PRGD/NLG919 nanosheets followed by laser irradiation, a more robust adaptive immune response occurred, leading to a substantial proliferation of CD3+CD8+ T cells and CD3+CD4+ T cells compared to control groups. Our pH-responsive targeted PRGD/NLG919 nanosheets therefore represent a promising nanosystem for combination therapy, offering effective PDT and an enhanced host immune response.

A self-assembled theranostic nanoplatform for efficient tumor sonodynamic-gas therapy

The powerful antioxidant system in tumor tissues limits the efficacy of sonodynamic therapy (SDT) by reducing the availability of the produced reactive oxygen species (ROS). To address this problem, a pH/ultrasound (US) responsive theranostic nanoplatform is elaborately constructed by self-assembly of nitrogen-doped graphene quantum dots (NGQDs), benzothiazole sulfinate (BTS), Gd3+ ions and poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG). The NGQD component with excellent sonodynamic activity wrapped in the resulting Gd-NGQDs/BTS@PLGA-PEG can efficaciously respond to ultrasonic irradiation and cause abundant ROS generation. Importantly, in response to acidic tumor microenvironment, the loaded BTS sustainably releases SO2, which induces the increase of intracellular •O2− level by inhibiting superoxide dismutase activity and further promotes the enrichment of ROS by reducing intracellular glutathione level and suppressing glutathione peroxidase 4 activity. The well-designed SO2 gas therapy-enhanced SDT strategy leads to high oxidative stress in tumor cells and effective inhibition of the growth of bilateral tumors with only a single intravenous injection of the nanomedicine and a subsequent single US irradiation. Gd-NGQDs/BTS@PLGA-PEG can also be employed as a good T1-weighted magnetic resonance imaging contrast agent to guide tumor therapy. This innovative therapeutic strategy developed in our contribution may provide a new paradigm for the exploration of deep tumor therapy.

Multienzyme-Like Polyoxometalate-Based Single-Atom Enzymes for Cancer-Specific Therapy Through Acid-Triggered Nontoxicity-to-Toxicity Transition.

Single-atom enzymes (SAzymes) exhibit great potential for chemodynamic therapy (CDT); while, general application is still challenged by their instability and unavoidable side effects during delivery. Herein, a manganese-based polyoxometalate single-atom enzyme (Mn-POM SAE) is first introduced into tumor-specific CDT, which exhibits tumor microenvironment (TME)-activated transition of nontoxicity-to-toxicity. Different from traditional POM materials, the aggregates of low-toxic Mn-POM SAE nanospheres are obtained at neutral conditions, facilitating efficient delivery and avoiding toxicity problems in normal tissues. Under acid TME conditions, these nanospheres are degraded into smaller units of toxic Mn(II)-PW11; thus, initiating cancer cell-specific therapy. The released active units of Mn(II)-PW11 exhibit excellent multienzyme-like activities (including peroxidase (POD)-like, oxidase (OXD)-like, catalase (CAT)-like, and glutathione peroxidase (Gpx)-like activities) for the synergistic cancer therapy due to the stabilized high valence Mn species (MnIII/MnIV). As demonstrated by both intracellular evaluations and in vivo experiments, ROS is generated to cause damage to lysosome membranes, further facilitating acidification and impaired autophagy to enhance cancer therapy. This study provides a detailed investigation on the acid-triggered releasing of active units and the electron transfer in multienzyme-mimic-like therapy, further enlarging the application of POMs from catalytical engineering into cancer therapy.

Ultrasound-visible engineered bacteria for tumor chemo-immunotherapy

Our previous work developed acoustic response bacteria, which enable the precise tuning of transgene expression through ultrasound. However, it is still difficult to visualize these bacteria in order to guide the sound wave to precisely irradiate them. Here, we develop ultrasound-visible engineered bacteria and chemically modify them with doxorubicin (DOX) on their surfaces. These engineered bacteria (Ec@DIG-GVs) can produce gas vesicles (GVs), providing a real-time imaging guide for remote hyperthermia high-intensity focused ultrasound (hHIFU) to induce the expression of the interferon (IFN)-γ gene. The production of IFN-γ can kill tumor cells, induce macrophage polarization from the M2 to the M1 phenotype, and promote the maturation of dendritic cells. DOX can be released in the acidic tumor microenvironment, resulting in immunogenic cell death of tumor cells. The concurrent effects of IFN-γ and DOX activate a tumor-specific Tcell response, producing the synergistic anti-tumor efficacy. Our study provides a promising strategy for bacteria-mediated tumor chemo-immunotherapy.