Inhibit Tumor Recurrence Research Articles

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Effect of NIR-II on cancer nanocomposite vaccines for lymph node targeted delivery and enhanced immunotherapy.

e20506 Background: Cancervaccines have become one of the hot areas of research in recent years. However, different types of tumors and the tumor tissue itself are heterogeneous. Some cancervaccines contain a single epitope and have weak immunogenicity. The antigen-presenting cells cannot adequately absorb and present the antigen peptide contained in the vaccine. As a result, the body fails to elicit an effective immune response, which greatly limits the therapeutic effect of the cancervaccine. In situ cancervaccines composed of antigens and adjuvants are a promising cancer treatment modality; however, convenient manufacturing of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remain a significant challenge. In this study, we outline a facile approach to simultaneously achieve in situ programming of vaccines via two synergistic nanomedicines to generate robust immune responses. Methods: We first prepared two synergistic nanocomposite systems: Gold nanorods, amphiphilic polymer polyphosphate mPEG- b-PHEP encapsulating the immune adjuvant R848, and nanoparticles doped with cationic liposomes DOTAP. Two nanomedicines were characterized and the efficacy of the nanovaccine was verified at the Cellular Experiments. At the animal level, the lymph node targeting of the nanoparticles was demonstrated through IVIS. We also constructed distant model and lung metastasis model to verify the nanovaccine's effect on enhancing systemic immunotherapy. Results: We used amphiphilic polymer polyphosphate mPEG- b-PHEP to encapsulate TLR7/8 agonist R848 to obtain VNPR848 nanoparticles. Gold nanorods (~ 100nm) can produce a strong photothermal effect mediated by NIR-II, killing tumor cells and releasing abundant antigens at the same time. The small size of VNPR848 (~ 30nm) is beneficial to the enrichment of lymph nodes. After capturing the antigens produced by photothermal, nanoparticles will be targeted and delivered to the tumor draining lymph nodes together with R848, and will be effectively absorbed by DC cells. This in situ tumor vaccine with the ability of targeted delivery of lymph nodes can trigger a strong anti-tumor immune response. This therapy can completely inhibit distant tumors in some mice and produce a long-term immune memory effect on NSCLC metastasis. Conclusions: We propose a simple personalized in situ cancervaccine strategy, which uses nanotechnology to remove tumors in situ and release antigens. Antigens and immune adjuvants are simultaneously delivered to the draining lymph nodes to initiate the antigen presentation function of DC cells, resulting in an anti-tumor immune response to inhibit tumor recurrence and metastasis. The nano-vaccine based on powerful therapeutic effect provides an attractive technology for in situ programming of personalized cancervaccine and an effective strategy for the development of cancervaccine.

Reinforcing Carrier‐Free Photothermal Nanodrugs Through Flavonol‐Driven Assembly

AbstractCarrier‐free nanodrugs that integrate chemodrugs and other therapeutic agents demonstrate good efficacy and minimized side effects, showing promise for combined therapy. However, a key challenge lies in enhancing the bioavailability and therapeutic potential of the nanodrugs through a controllable assembly process. Herein, a carrier‐free photothermal nanodrug (ZPQ NPs) is constructed through flavonol‐driven assembly with amine‐substituted perylene diimide for enhanced chemo‐photothermal combined cancer therapy. The flavonol, particularly quercetin, facilitates J‐aggregation of perylene diimide derivatives within the nanodrug and contributes to multiple improvements, including red‐shifted absorption, enhanced fluorescence intensity, improved photothermal conversion efficiency as well as excellent photostability. Moreover, the nanodrug also demonstrates enhanced cellular uptake and intracellular reactive oxygen species scavenging capability. The combination of quercetin and photothermal effect effectively kills cancer cells, as well as alleviates inflammation following photothermal therapy. Guided by in vivo fluorescence imaging, the application of ZPQ NPs results in complete tumor elimination and effectively inhibits tumor recurrence through chemo‐photothermal combined therapy. This work presents a straightforward strategy for constructing carrier‐free nanodrugs that exhibit simultaneous enhancements in both photophysical properties and biological activity.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

Biomimetic Tertiary Lymphoid Structures with Microporous Annealed Particle Scaffolds for Cancer Postoperative Therapy.

Immunotherapy plays a vital role in cancer postoperative treatment. Strategies to increase the variety of immune cells and their sustainable supply are essential to improve the therapeutic effect of immune cell-based immunotherapy. Here, inspired by tertiary lymphoid structures (TLSs), we present a microfluidic-assisted microporous annealed particle (MAP) scaffold for the persistent recruitment of diverse immune cells for cancer postoperative therapy. Based on the thermochemical responsivity of gelatin methacryloyl (GelMA), the MAP scaffold was fabricated by physical cross-linking and sequential photo-cross-linking of GelMA droplets, which were prepared by microfluidic electrospraying. Due to the encapsulation of liquid nitrogen-inactivated tumor cells and immunostimulant, the generated MAP scaffold could recruit a large number of immune cells, involving T cells, macrophages, dendritic cells, B cells, and natural killer cells, thereby forming the biomimetic TLSs in vivo. In addition, by combination of immune checkpoint inhibitors, a synergistic anticancer immune response was provoked to inhibit tumor recurrence and metastasis. These properties make the proposed MAP scaffold-based artificial TLSs of great value for efficient cancer postoperative therapy.

Investigating the effect of tannin films prepared by low-energy electron beam deposition on the inhibition of bone tumors

Osteosarcoma is a prevalent malignant bone tumor and incomplete surgical resection of the tumor often results in higher rates of local recurrence. To tackle this issue, there is an urgent requirement to develop implants that possess the capability to inhibit tumor recurrence. In this paper, we prepared three different thicknesses of tannin (TA) films on titanium substrates using low-energy electron beam deposition to study their effects on bone tumor inhibition. The structure and morphology of TA films were analyzed by FT-IR, XPS, SEM, and EDX. The release kinetics of tannins were investigated, revealing their ability to achieve sustained release. This sustained release is advantageous for long-term inhibition of bone tumors. Cellular experiments, including cytotoxicity test, live/dead double staining, cell migration and western blot, were performed to evaluate the tumor-suppressing activity of TA films in vitro. The results indicated that the TA films were not only non-cytotoxic to normal bone cells, but also exhibited excellent in vitro anti-tumor activity by effectively inhibiting the activity and migration of bone tumor cells.

Improving the predictive accuracy of efficacy evaluation using tumor orthotopic transplant and resection model.

Preclinical efficacy evaluation and tumor drug sensitivity analysis are two main applications of efficacy evaluation. Preclinical efficacy evaluation is to predict whether candidate drugs or therapies may improve patient outcomes in clinical trials. Tumor drug sensitivity analysis is an approach for the personalized evaluation and optimization of approved anti-cancer drugs and treatment regimens. Overall survival (OS) is the gold standard to evaluate the outcome of drugs or therapies in both clinical trials and clinical treatment. Many efficacy evaluation models, such as cell model, tumor cell-line transplant model, patient-derived tumor xenograft model, tumor organoid model, have been developed to assess the inhibitory effect of tested drugs or therapies on tumor growth. In fact, many treatments may also lead to malignant progression of tumors, such as chemotherapy, which can lead to metastasis. Therefore, tumor growth inhibition does not necessarily predict OS benefit. Whether it can prevent or inhibit tumor recurrence and metastasis is the key to whether drugs and therapies can improve patient outcomes. In this perspective, we summarize the current understanding of the pathological progression of tumor recurrence and metastasis, point out the shortcomings of existing tumor transplant models for simulating the clinical scenario of malignant progression of tumors, and propose five improved indicators for comprehensive efficacy evaluation to predict OS benefit using tumor orthotopic transplant and resection model. Improvement in the accuracy of efficacy evaluation will accelerate the development process of anti-cancer drugs or therapies, optimize treatment regimens to improve OS benefit, and reduce drug development and cancer treatment costs.

Nitric oxide polymersome-immobilized hydrogels for prevention of post-surgical tumor recurrence and metastasis

Surgical resection is the primary means of tumor treatment. However, postoperative tumors are prone to recurrence and metastasis due to residual tumor cells and complicated post-surgical microenvironments. The absence of effective intervention strategies for regulating the recurrent tumor microenvironment frequently leads to unfavorable prognostic outcomes. To address this issue, a biodegradable nitric oxide donor (NO) polymersome-immobilized hydrogel platform (NO-GEL) was constructed by using biodegradable functional polycarbonates. The polymersomes from NO-GEL were utilized to load immune checkpoint inhibitors of anti-programmed cell death protein 1 antibody (αPD1) for synergistic postoperative cancer therapy. The αPD1-loaded NO-GEL (NO-GEL@αPD1) was characterized with reduction-responsive NO and αPD1 release in the emergence of recurrent tumor exhibiting gas/immunotherapeutic activity via NO-mediated microenvironment reprogramming and immune checkpoint blocking. More importantly, covalent-embedded polymersomes in the hydrogel prevented the endocytosis of αPD1 and increased the therapeutic efficiency for cell membrane target inhibition. The hybrid structure further avoided the sudden release of cargos and realized the on-demand release of bioactive agents when exposed to recurrent tumor cells. The in vivo results demonstrated that the platform could effectively inhibit tumor recurrence and metastasis on mouse models, suggesting a high potential for the combined treatment of postoperative tumor recurrence and metastasis.

Biomimetic Nano-Cancer Stem Cell Scavenger for Inhibition of Breast Cancer Recurrence and Metastasis after FLASH-Radiotherapy.

Compared to conventional radiotherapy (RT), FLASH-RT delivers ultra-high dose radiation, significantly reducing damage to normal tissue while guaranteeing the effect of cancer treatment. However, cancer recurrence and metastasis frequently occur after all RT due to the existence of intractable cancer stem cells (CSCs). To address this, a biomimetic nanoplatform (named TAFL) of tumor-derived exosome fusion liposomes is designed by co-loading aggregation-induced emission photothermal agents, TPE-BBT, and anti-cancer drugs, aspirin, aiming to clear CSCs for inhibiting cancer recurrence and metastasis after FLASH-RT therapy . Aspirin released in TAFL system triggered by laser irradiation can induce apoptosis and DNA damage of 4T1 CSCs, comprehensively downregulate their stemness phenotype, and inhibit their sphericity. Furthermore, the TPE-BBT mediated mild-photothermal therapy can alleviate the hypoxic tumor microenvironment, inhibit the DNA repair of CSCs, which further amplifies the effect of aspirin against CSCs, therefore reduces the effective dose of aspirin, making TAFL more biologically safe. In vivo experimental results demonstrated that decreased CSCs population mediated by TAFL systemtreatment significantly inhibited tumor recurrence and metastasis after FLASH-RT therapy. In summary, this TAFL system provides a new idea for the future clinical application of FLASH-RT therapy.

Thermo-sensitive PLGA-PEG-PLGA hydrogel for sustained release of EGF to inhibit cervical cancer recurrence

Overexpression of epidermal growth factor receptor (EGFR) in cancer is a key cause of recurrence of cervical cancer (CC). Although the EGF-EGFR pathway has been studied for decades, preventing tumor growth and recurrence caused by peripheral EGF remains a great challenge. In this work, a strategy is proposed to reduce the stimulation of high concentration EGF on tumor growth by using a thermo-sensitive hydrogel. The hydrogel is a triblock copolymer composed of polyethylene glycol (PEG) and poly (lactide glycolide) (PLGA). Based on the excellent temperature sensitivity, carrier capacity, swelling property and biocompatibility, the hydrogel can absorb the liquid around the tumor by injection and release EGF continuously at low concentration. The inhibitory effect of hydrogel on tumor growth is fully confirmed by an implanted tumor mouse model with human cervical cancer cell lines (HeLa) using triple-immunodeficient NCG mice. Compared with free EGF, the EGF-loaded hydrogel can hardly induce surface plasmon resonance (SPR) response, which proves that hydrogel can effectively weaken cytoskeleton rearrangement and inhibit cell migration by continuously releasing low concentration EGF. In addition, the EGF-loaded hydrogel can reduce cell proliferation by delaying the progress of cell cycle progression. Taken together, the hydrogel can effectively protect tumor microenvironment from the stimulation of high concentration EGF, delay cancer cellular processes and tumor growth, and thus providing an approach for inhibiting tumor recurrence of CC.

Hybrid Ginseng-derived Extracellular Vesicles-Like Particles with Autologous Tumor Cell Membrane for Personalized Vaccination to Inhibit Tumor Recurrence and Metastasis.

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

Injectable hydrogel with antimicrobial and anti-inflammatory properties for postoperative tumor wound care.

Clinically, tumor removal surgery leaves irregularly shaped wounds that are susceptible to bacterial infection and further lead to excessive inflammation. Injectable hydrogel dressings with antimicrobial and anti-inflammatory properties have been recognized as an effective strategy to care for postoperative tumor wounds and prevent recurrence in recent years. In this work, we constructed a hydrogel network by ionic bonding interactions between quaternized chitosan (QCS) and epigallocatechin gallate (EGCG)-Zn complexes which were coordinated by EGCG and zinc ions. Because of the synergistic effect of QCS and EGCG-Zn, the hydrogel exhibited outstanding antimicrobial capacity (>99.9% inhibition), which could prevent infections caused byEscherichia coli and Staphylococcus aureus. In addition, the hydrogel was able to inhibit the growth of mice breast cancer cells (56.81% survival rate within 72 h) and reduce inflammation, which was attributed to the sustained release of EGCG. The results showed that the hydrogel was effective in inhibiting tumor recurrence and accelerating wound closure when applied to the postoperative tumor wounds. This study provided a simple and reliable strategy for postoperative tumor wound care using antimicrobial and anti-inflammatory injectable dressings, confirming their great potential in the field of postoperative wound dressings.

Inflammation-Driven Nanohitchhiker Enhances Postoperative Immunotherapy by Alleviating Prostaglandin E2-Mediated Immunosuppression.

Inflammation contributes to the immunosuppressive microenvironment and leads to the recurrence of surgically resected tumors. The COX-2/PGE2 axis is considered a key player in shaping the immunosuppression microenvironment. However, targeted modulation of the postoperative tumor microenvironment is challenging. To specifically curb the inflammation and alleviate immunosuppression, here, we developed a PGE2 inhibitor celecoxib (CXB)-loaded bionic nanoparticle (CP@CM) coated with activated murine vascular endothelial cell (C166 cells) membrane to target postoperative melanoma and inhibit its recurrence. CP@CM adhered to inflammatory white blood cells (WBCs) through the adhesion molecules, including ICAM-1, VCAM-1, E-selectin, and P-selection, expressed on the surface of C166 cells. Leveraging the natural tropism of the WBC to the inflammatory postoperative tumor site, CP@CM efficiently targeted postoperative tumors. In melanoma postoperative recurrence models, CXB significantly reduced PGE2 secretion and the recruitment of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) by inhibiting the activity of COX-2. This was followed by an increase in the infiltration of CD8+ T cells and CD4+ T cells in tumor tissues. Additionally, the immune responses were further enhanced by combining a PD-L1 monoclonal antibody. Ultimately, this immunotherapeutic strategy reversed the tumor immunosuppressive microenvironment and inhibited tumor recurrence, demonstrating a promising potential for postoperative immunotherapy for melanoma.

Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. Statement of significanceThe limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8pgmL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

An Intelligent DNA Nanoreactor for Easy‐to‐Read In Vivo Tumor Imaging and Precise Therapy

AbstractNanomaterial‐based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent “always ON” or single‐parameter responsive signal output, substantial off‐target effects, and high cost. Therefore, achieving in vivo easy‐to‐read tumor imaging and precise therapy in a multi‐parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the “AND” Boolean logic algorithm to address these issues. iDNR‐mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers “AND” hydrogen peroxide (H2O2). Therefore, intelligent temperature‐based in vivo easy‐to‐read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.

An Intelligent DNA Nanoreactor for Easy-to-Read In Vivo Tumor Imaging and Precise Therapy.

Nanomaterial-based in vivo tumor imaging and therapy have attracted extensive attention; however, they suffer from the unintelligent "always ON" or single-parameter responsive signal output, substantial off-target effects, and high cost. Therefore, achieving in vivo easy-to-read tumor imaging and precise therapy in a multi-parameter responsive and intelligent manner remains challenging. Herein, an intelligent DNA nanoreactor (iDNR) was constructed following the "AND" Boolean logic algorithm to address these issues. iDNR-mediated in situ deposition of photothermal substance polydopamine (PDA) can only be satisfied in tumor tissues with abundant membrane protein biomarkers "AND" hydrogen peroxide (H2 O2 ). Therefore, intelligent temperature-based in vivo easy-to-read tumor imaging is realized without expensive instrumentation, and its diagnostic performance matches with that of flow cytometry, and photoacoustic imaging. Moreover, precise photothermal therapy (PTT) of tumors could be achieved via intelligent heating of tumor tissues. The precise PTT of primary tumors in combination with immune checkpoint blockade (ICB) therapy suppresses the growth of distant tumors and inhibits tumor recurrence. Therefore, highly programmable iDNR is a powerful tool for intelligent biomedical applications.

ROS-responsive thermosensitive polypeptide hydrogels for localized drug delivery and improved tumor chemoimmunotherapy.

In this study, we developed a ROS-responsive thermosensitive poly(ethylene glycol)-polypeptide hydrogel loaded with a chemotherapeutic drug, doxorubicin (Dox), an antiviral imidazoquinoline, resiquimod (R848), and antibody targeting programmed cell death protein 1 (aPD-1) for local chemoimmunotherapy. The hydrogel demonstrated controllable degradation and sustained drug release behavior according to the concentration of ROS in vitro. Following intratumoral injection into mice bearing B16F10 melanoma, the Dox/R848/aPD-1 co-loaded hydrogel effectively inhibited tumor growth, prolonged animal survival time and promoted anti-tumor immune responses with low systemic toxicity. In the postoperative model, the Dox/R848/aPD-1 co-loaded hydrogel exhibited enhanced tumor recurrence prevention and long-term immune memory effects. Thus, the hydrogel-based local chemoimmunotherapy system demonstrates potential for effective anti-tumor treatment and suppression of tumor recurrence.

Fructose-mineralized black phosphorus for syncretic bone regeneration and tumor suppression.

Black phosphorus (BPs) nanosheets with their inherent and selective chemotherapeutic effects have recently been identified as promising cancer therapeutic agents, but challenges in surface functionalization hinder satisfactory enhancement of their selectivity between tumors and normal cells. To address this issue, we developed a novel biomineralization-inspired strategy to synthesize CaBPs-Na2FDP@CaCl2 nanosheets, aiming to achieve enhanced and selective anticancer bioactivity along with accelerated osteoblast activity. Benefiting from the in situ mineralization and fructose modification, CaBPs-Na2FDP@CaCl2 exhibited improved pH-responsive degradation behavior and targeted therapy for osteosarcoma. The in vitro results indicated that CaBPs-Na2FDP@CaCl2 exhibited efficient uptake and quick degradation by GLUT5-positive 143B osteosarcoma cells, enhancing BPs-driven chemotherapeutic effects through ATP level disturbance-mediated apoptosis of tumor cells. Moreover, CaBPs-Na2FDP@CaCl2 underwent gradual degradation into PO43-, Ca2+ and fructose in MC3T3-E1 cells, eliminating systemic toxicity. Intracellular Ca2+ bound to calmodulin (CaM), activating Ca2+/CaM-dependent signaling cascades, thereby enhancing osteoblast differentiation and mineralization in pro-osteoblastic cells. In vivo experiments affirmed the anti-tumor capability, inhibition of tumor recurrence and bone repair promotion of CaBPs-Na2FDP@CaCl2. This study not only broadens the application of BPs in bone tumor therapy but also provides a versatile surface functionalization strategy for nanotherapeutic agents.

Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer.

Rationale: Multiple copies in T-cell malignancy 1 (MCT-1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, which promotes epithelial-to-mesenchymal transition and cancer stemness. Because cancer stemness largely contributes to the tumor metastasis and recurrence, we aimed to identify whether the blockade of MCT-1 and IL-6R can render these effects and to understand the underlying mechanisms that govern the process. Methods: We assessed primary tumor invasion, postsurgical local recurrence and distant metastasis in orthotopic syngeneic mice given the indicated immunotherapy and MCT-1 silencing (shMCT-1). Results: We found that shMCT-1 suppresses the transcriptomes of the inflammatory response and metastatic signaling in TNBC cells and inhibits tumor recurrence, metastasis and mortality in xenograft mice. IL-6R immunotherapy and shMCT-1 combined further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. shMCT-1 also enhances IL-6R-based immunotherapy effectively in preventing postsurgical TNBC metastasis, recurrence and mortality. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in the lymphatic system and decreased Tregs in the recurrent and metastatic tumors. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity to a greater extent than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome and lowest postoperative recurrence and metastasis compared with synchronized therapy, particularly in the shMCT-1 context. Multiple positive feedforward loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boosted metastatic niches and immunosuppressive microenvironments. Clinically, MCT-1high/PD-L1high/CXCL7high and CXCL7high/IL-6high/IL-6Rhigh expression patterns predict worse prognosis and poorer survival of breast cancer patients. Conclusion: Systemic targeting the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnections enhances immune surveillance that inhibits the aggressiveness of TNBC.