Macrophage Repolarization Research Articles

Iron-glucose oxidase nanogel assembly for amplified starvation-ferroptosis anti-tumor therapy.

Developing advanced and effective enzyme-drug systems for cancer treatment is of significant interest. Herein, a novel approach is reported to create a highly active and robust enzyme-drug system. Glucose oxidase nanogels (nGOx) are first synthesized by polymerization on the surface of GOx using vinylimidazole as comonomers. Fe3+ are utilized to induce self-assembly of nGOx through the imidazole-metal coordination interaction to form GOx nanogel clusters (Fe@nGOx), enhancing the permeability and retention of nGOx into tumor cells by EPR effect. nGOx can deplete glucose in the presence of oxygen and generate H2O2, which is converted to highly cytotoxic hydroxyl radical (·OH) by Fe3+ and GSH, and the proximity between Fe3+ and GOx act in tandem for enhanced tumor therapy. The FeIII/FeII redox cycle reacts with GSH and H2O2, enabling continuous generation of ·OH within tumor cells, thus facilitating the anticancer effect. Moreover, the generation of H2O2 and ·OH can further promote the repolarization of tumor-associated macrophages from an M2 phenotype towards an M1 phenotype polarization, thus enhancing immune response. The cascade reaction between GOx and Fe3+/Fe2+ endows Fe@nGOx with excellent anti-tumor efficacy in mice models, highlighting its potential as a promising anticancer drug for clinical applications. This work establishes a new platform for utilizing enzyme/protein and metal ion complexes in versatile applications, advancing the field of enzyme-based cancer therapies.

Locally administered liposomal drug depot enhances rheumatoid arthritis treatment by inhibiting inflammation and promoting cartilage repair

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by synovial hyperplasia, where inflammatory macrophages within the joint synovium produce multiple inflammatory cytokines, leading to cartilage damage. The development of therapeutic strategies that combine anti-inflammatory effects and cartilage repair mechanisms holds great promise for effective RA treatment. To address the limitations associated with the off-target effects of intravenous administration and the risk of synovial cavity infection with repeated local injections, we have innovatively developed a liposomal drug depot through hyaluronic acid (HA)-modified liposomes encapsulating dexamethasone sodium phosphate (DSP)-loaded nanogels, termed HA-Lipo@G/D. The nanogels were prepared by ionic cross-linking of chondroitin sulfate and gelatin, both of which have notable cartilage repair properties. In vitro studies demonstrated that this formulation exhibited sustained drug release, enhanced uptake by inflammatory macrophages, reduced secretion of inflammatory factors (TNF-α, IL-1β), and significantly decreased chondrocyte apoptosis induced by inflammatory factors. Moreover, in vivo assessments in a rat model of collagen-induced arthritis revealed effective accumulation of the liposomal drug depot at the inflamed joint site, resulting in macrophage repolarization and cartilage tissue repair. Our findings provide a synergistic strategy for inhibiting inflammation and mitigating cartilage damage through local joint cavity injection, thereby enhancing the therapeutic efficacy of RA.Graphical

Defect-Engineered Biomimetic Piezoelectric Nanocomposites With Enhanced ROS Production, Macrophage Re-polarization, and Ca2+ Channel Activation for Therapy of MRSA-Infected Wounds and Osteomyelitis.

Antibiotic-resistant bacteria often cause lethal infections in both the surficial and deep organs of humans. Failure of antibiotics in resistant infections leads to more effective alternative therapies, like spatiotemporally controllable piezodynamic therapy (PZDT) with deep penetration. Currently, PZDT demands further investigation for improved treatment outcomes and the corresponding therapeutic mechanisms. Herein, a nanocomposite cloaked is reported with a biomimetic coating of TLR-upregulated macrophage membrane for targeted PZDT against MRSA-induced skin wound infection and osteomyelitis, representing surficial and deep infection models, respectively. To boost the therapeutic efficacy, crystal defect engineering is applied by impregnating Fe2+ into bismuth oxy-iodide nanosheets to increase the crystal defects. This results in a significantly higher piezoelectric coefficient than in previous reports, contributing to an amplified reactive oxygen species generation for bacterial killing. More importantly, the notable piezoelectric effect not only re-programs the macrophages into ananti-inflammatory M2 phenotype for accelerating bacterial wound healing but also stimulates the opening of the piezo-stimulated Ca2+ channels and boosts the differentiation of mesenchymal stem cells into osteoblasts for expediting bone tissue repair in osteomyelitis model. Moreover, the Fe-doping supplements T2-magnetic resonance imaging for real-time visualization of nanocomposite distribution. This theranostic system opens a new avenue for future treatment of drug-resistant bacteria-caused diseases.

Effectively alleviate rheumatoid arthritis via maintaining redox balance, inducing macrophage repolarization and restoring homeostasis of fibroblast-like synoviocytes by metformin-derived carbon dots

Overproduction of reactive oxygen species (ROS), elevated synovial inflammation, synovial hyperplasia and fibrosis are the main characteristic of microenvironment in rheumatoid arthritis (RA). Macrophages and fibroblast-like synoviocytes (FLSs) play crucial roles in the progression of RA. Hence, synergistic combination of ROS scavenging, macrophage polarization from pro-inflammatory M1 phenotype towards M2 anti-inflammatory phenotype, and restoring homeostasis of FLSs will provide a promising therapeutic strategy for RA. In this study, we successfully synthesized metformin-derived carbon dots (MCDs), and investigated the antirheumatic effect in vivo and in vitro. Designed MCDs could target inflamed cells and accumulate at the inflammatory joints of collagen-induced arthritis (CIA) rats. In vivo therapeutic investigation suggested that MCDs reduced synovial inflammation and hyperplasia, ultimately prevented cartilage destruction, bone erosion, and synovial fibrosis in CIA rats. In addition, MCDs eliminated the cellular ROS in M1 phenotype macrophages in RA microenvironment through the enzyme-like catalytic activity as well as inhibiting NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome signaling pathway, effectively polarizing them into the M2 phenotype to realize the anti-inflammatory effect. Furthermore, MCDs could inhibit the proliferation, migration, and fibrosis of inflamed FLSs. Mechanistically, MCDs restored the homeostasis of FLSs while reducing the level of synovial inflammation by blocking IL-6/gp130 signaling pathway. Combined with preferable biocompatibility, MCDs offer a prospective treatment approach for RA.

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1-mediated M1 macrophage polarization and fosters Staphylococcus aureus control

In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2 response, including M2 macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages toward the M1 phenotype may foster control of S. aureus. Our data show that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1 macrophage polarization by K63-specific deubiquitination of STAT1 and activation of the NF-κB pathway via its interaction with TRAF6, NEMO, and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and CYLD-competent M1 macrophages. Infection of Cyld-deficient and wild-type mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients, identifying CYLD as a potential therapeutic target.

Dual Targeting Biomimetic Carrier-Free Nanosystems for Photo-Chemotherapy of Rheumatoid Arthritis via Macrophage Apoptosis and Re-Polarization.

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease that often results in irreversible joint erosion and disability. Methotrexate (MTX) is the first-line drug against RA, but the significant side effects of long-term administration limit its use. Therefore, new therapeutic strategies are needed for treating RA. Here, dual-targeting biomimetic carrier-free nanomaterials (BSA-MTX-CyI nanosystem, BMC) is developed for synergistic photo-chemotherapy of RA. Bovine serum albumin (BSA), which has high affinity with SPARC (secreted protein acidic and rich in cysteine) in the RA joint microenvironment, is selected as the hydrophilic end and coupled with MTX and the phototherapeutic agent CyI to self-assemble into BMC. In vitro and in vivo experiments revealed that BMC accumulated significantly at the joint site in collagen antibody-induced arthritis mice and could be specifically recognized and taken up by folate receptors in proinflammatory M1 macrophages. Upon near-infrared laser irradiation, CyI exerted photodynamic and photothermal effects, whereas MTX not only inhibited cell proliferation but also increased cell sensitivity to reactive oxygen species, enhancing the apoptotic effect induced by CyI and achieving synergistic photo-chemotherapy. Moreover, BMC could induce macrophages to reprogram into anti-inflammatory M2 macrophages. This study provides innovative approaches for RA treatment via macrophage apoptosis and re-polarization.

Suberosin attenuates rheumatoid arthritis by repolarizing macrophages and inhibiting synovitis via the JAK/STAT signaling pathway

BackgroundRheumatoid arthritis (RA) is a systemic disease that primarily manifests as chronic synovitis of the symmetric small joints. Despite the availability of various targeted drugs for RA, these treatments are limited by adverse reactions, warranting new treatment approaches. Suberosin (SBR), isolated from Plumbago zeylanica—a medicinal plant traditionally used to treat RA in Asia—possesses notable biological activities. This study aimed to investigate the effects and potential underlying pathways of SBR on RA.MethodsTumor necrosis factor-alpha (TNF-α) induced inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS), and the expression of proinflammatory mediators was assessed using q-RT PCR and ELISA after treatment with various SBR concentrations. Bone marrow-derived macrophages (BMDMs) were induced to differentiate into M1 and M2 macrophages, followed by treatment with various SBR concentrations and macrophage polarization assessment. Low-dose (0.5 mg/kg/d) and high-dose (2 mg/kg/d) SBR regimens were administered to a collagen-induced arthritis (CIA) mouse model for 21 days, and the anti-arthritic effects of SBR were evaluated. Network pharmacology and molecular docking analyses were used to predict the anti-arthritic targets of SBR. The effect of SBR on the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was evaluated.ResultsSBR suppressed macrophage polarization toward the M1 phenotype while enhancing their polarization toward the M2 phenotype. SBR reduced the levels of proinflammatory mediators in TNF-α-induced RA-FLS. Mechanistically, SBR inhibited the phosphorylation of the JAK1/STAT3 signaling pathway in RA-FLS and M1 macrophages and promoted the phosphorylation of the JAK1/STAT6 pathway in M2 macrophages, enhancing M2 polarization. In vivo, prophylactic treatment of low-dose SBR reduced M1 macrophage infiltration into synovial tissue, increased the proportion of M2 macrophages, and decreased the expression of inflammatory mediators in the serum and synovial tissue, alleviating synovial inflammation. SBR significantly alleviated arthritis in CIA mice through macrophage repolarization and inhibition of inflammation.ConclusionSBR significantly reduced clinical symptoms, joint pathological damage, and expression inflammatory cytokine expression in CIA mice. SBR exhibited anti-arthritic effects via the JAK1/STAT3 and JAK1/STAT6 signaling pathways, inhibiting synovial tissue inflammation and M1 macrophage polarization while promoting M2 macrophage polarization. Therefore, SBR may be an effective candidate for RA treatment.

Manganese dioxide-based in situ vaccine boosts antitumor immunity via simultaneous activation of immunogenic cell death and the STING pathway.

In situ vaccine (ISV) can activate the anti-tumor immune system by inducing immunogenic cell death (ICD) at the tumor site. However, the development of tumor ISV still faces challenges due to insufficient tumor antigens released by tumor cells and the existence of tumor immunosuppressive microenvironment (TIME). Targeting the STING pathway has been reported to enhance the adjuvant effects of in situ tumor vaccines by initiating innate immunity. Based on this, we developed a potent in situ cancer vaccine, MBMA-RGD ISV, which simultaneously induces ICD and activates the STING pathway to achieve sustained anti-tumor immunity. Specifically, a water-soluble prodrug Mit-ALA was synthesized from the chemotherapeutic agent mitoxantrone (Mit) and the photosensitizer precursor 5-aminolevulinic acid (5-ALA) by pH-responsive ester bonds, which was then loaded into pre-synthesized BSA-MnO2 nanoparticles and functionalized with the targeting Arg-Gly-Asp (RGD) peptide to obtain MBMA-RGD ISV. This ISV actively targets tumor cells by binding integrin receptors and then gradually releases antitumor components in response to tumor microenvironment (TME). The released 5-ALA is metabolized in mitochondria to produce photosensitizer PpIX. Under laser irradiation, the photodynamic property of PpIX coupled with the photothermal effect of Mit synergistically induced ICD, resulting in the release of tumor antigens and evoking adaptive immunity. Meanwhile, released Mn2+ and Mit synergistically activate the STING pathway by inducing DNA damage, further enhancing antitumor immunity. Moreover, large amounts of oxygen released by MnO2 relieved the hypoxia microenvironment, thus sensitizing photodynamic therapy and improving the immunosuppressive state of TME. Therefore, MBMA-RGD ISV efficiently activates systemic antitumor immunity in vitro and in vivo, providing new strategies and ideas for the development of tumor ISV. STATEMENT OF SIGNIFICANCE: Using a biocompatible BSA-MnO2 nanoplatform, we developed a dual-prodrug tumor in situ vaccine (ISV) with tumor microenvironment-responsive action for synergistic cancer immunotherapy. Once internalized by tumor cells, the MBMA-RGD ISV responded to intracellular H+, H2O2, and GSH, releasing its therapeutic "cargo." Under laser irradiation, the combined effects of photodynamic therapy (PDT) and photothermal therapy (PTT) induced immunogenic cell death (ICD), effectively recruiting and stimulating dendritic cells (DCs). Concurrently, STING pathway activation, triggered by DNA damage, enhanced DC maturation. Moreover, the MnO2 component alleviated hypoxia within the tumor microenvironment by releasing significant amounts of oxygen, which facilitated the repolarization of macrophages from the M2 phenotype to the M1 phenotype. Therefore, MBMA-RGD ISV demonstrated potent suppression of tumor metastasis and recurrence without notable side effects in mouse tumor models.

Biomimetic Diselenide-Sonosensitizer Nanoplatform for Enhanced Sonodynamic Therapy and In Situ Remodeling Immunosuppressive Microenvironment via Activating Innate and Adaptive Immunotherapy.

Sonodynamic therapy (SDT), which is non-invasive and controllable has the potential to treat triple-negative breast cancer (TNBC). However, the hypoxia and immunosuppressive tumor microenvironment (TME) often block the production of reactive oxygen species and the induction of SDT-activated immunogenic cell death, thus limiting the activation of adaptive immune responses. To alleviate these challenges, we proposed the development of a multifunctional biomimetic nanoplatform (mTSeIR), which was designed with diselenide-conjugated sonosensitizers and tirapazamine (TPZ), encapsulated within M1 macrophage membrane. This nanoplatform utilized hypoxia-induced chemotherapy to improve the efficacy of SDT, to further enhance adaptive immunotherapy by activating innate immunity and remodeling the immunosuppressive TME. Firstly, the prodrug TPZ was activated due to the increased oxygen consumption associated with SDT. Subsequently, the mTSeIR enhanced repolarization of M2 macrophages to the M1 phenotype. The diselenide component in mTSeIR effectively activated the natural killer cell-mediated antitumor innate immune response. Ultimately, in vivo studies indicated that mTSeIR+US with good biosafety achieved over 98% tumor inhibition and enhanced adaptive immunotherapy. This research presents an efficient approach that addressed the limitations of SDT and achieves simultaneous activation of both innate and adaptive immunotherapy, resulting in significant antitumor and anti-metastatic efficacy in TNBC.

Facile integration of a binary nano-prodrug with αPD-L1 as a translatable technology for potent immunotherapy of TNBC.

Immune checkpoint blockers (ICBs)-based immunotherapy is a favorable approach for efficient triple-negative breast cancer (TNBC) treatment. However, the therapeutic efficacy of ICBs is greatly compromised by immunosuppressive tumor microenvironments (TMEs) and low expression levels of programmed cell death ligand-1 (PD-L1). Herein, we constructed an amphiphilic prodrug by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond, which can self-assemble into GEM-MSA-2 (G-M) nanoparticles (NPs) with a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Notably, the immunogenic cell death (ICD)-triggering effect of GEM together with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation properties of MSA-2 enables efficient infiltration of non-exhausting T cells and repolarization of macrophages from M2 to M1 types in the tumor microenvironment for transforming a cold tumor to a hot one. Most importantly, G-M NPs treatment increases the PD-L1 expression levels, thus providing a unique opportunity for further integration with anti-PD-L1 monoclonal antibody (αPD-L1) for eliciting stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge. Overall, this study presents a minimalist nano-prodrug combined with αPD-L1 as a simple yet robust translatable nanotechnology for potent chemo-immunotherapy of TNBC. STATEMENT OF SIGNIFICANCE: Enhancing the therapeutic efficacy of αPD-L1 for tumor immunotherapy via a translatable technology remains a challenge. We report herein facile integration of a binary nano-prodrug with αPD-L1 for potent immunotherapy of TNBC. An amphiphilic prodrug is constructed by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond. The resulting self-assembled GEM-MSA-2 (G-M) nanoparticles (NPs) show a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Besides the induced immunogenic cell death (ICD) and activated cGAS-STING pathway, G-M NPs increase the PD-L1 expression levels, providing a unique opportunity for further integration with αPD-L1 to elicit stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge.

Deficiency of myeloid discoidin domain receptor 2 aggravates melanoma lung and bone metastasis.

Melanoma, one of the most prevalent cancers worldwide, frequently metastasizes to the lung and bones. Tumor-associated macrophages play essential roles in melanoma metastasis but the underlying mechanism remains obscure. We previously demonstrated that specific knockout of Ddr2, a receptor tyrosine kinase, exacerbates systemic inflammation via modulating macrophage repolarization. To investigate whether myeloid Ddr2 regulates melanoma growth and metastasis, we injected B16BL6 melanoma cells into Ddr2LysM (cKO) mice via subcutaneous neck, tail vein, and left ventricle, respectively. We found that the growth of melanoma cells in cKO mice was significantly retarded, as demonstrated by the subcutaneous transplantation tumor model. Unexpectedly, the melanoma metastasis to the lung or bone was significantly stimulated in cKO mice, indicating the complicated role of Ddr2 in macrophages in melanoma development. Furthermore, Ddr2 in macrophages regulated the migration of B16BL6 cells in the co-culture system. Bioinformatics analysis showed that Ddr2 expression correlates with improved prognostic outcomes in melanoma, and high expression of Ddr2 is protective in melanoma metastasis. Our results enrich the current knowledge of Ddr2 in tumor biology and indicate that more consideration should be taken when applying Ddr2 inhibition as a melanoma treatment strategy.

Hydrolysis of 2D Nanosheets Reverses Rheumatoid Arthritis Through Anti-Inflammation and Osteogenesis.

Rheumatoid arthritis (RA) is a kind of inflammation homeostasis disorder that dysfunctions the joints. Clinically, medications against RA focus simply on mitigating the focal inflammation, without considering pro-osteogenesis re-modeling of the bone microenvironment. In the present work, 2D layered calcium disilicide nanoparticles (CSNs) are fabricated by facile aqueous exfoliation. The hydrolysis of CSNs produces anti-oxidative H2, alkaline Ca(OH)2, and silica. These moieties play significant roles in anti-oxidation, anti-inflammation, and pro-osteogenesis resulting inconsiderably better RA therapeutic consequences than anti-inflammation alone. Hydrogen gas is validated to eliminate excessive hydroxyl radicals and regulate macrophage re-polarization; the generated Ca(OH)2 can neutralize the acidic microenvironment and inhibit the osteoclast activity; and, the dissolved Ca2+ can effectively complex with phosphates to mineralize Ca3(PO4)2, promoting the osteogenesis of the focal joint. The multifunctional performances of CSNs are further confirmed in arthritic mouse and rabbit models, providing an advanced and robust therapeutic strategy against RA with high biocompatibility and clinical transformable promises.

Advances in Tumor Inhibition by Repolarized M2 Macrophages

The tumor microenvironment (TME) plays a crucial role in the occurrence, growth, and metastasis of tumors. Tumor-associated macrophages (TAMs), derived from bone marrow precursor cells, exhibit functional plasticity by polarizing into either pro-tumor M2 or anti-tumor M1 phenotypes depending on the microenvironment. This paper explores the advantages and limitations of targeted drug delivery systems using nanocarriers for the repolarization of M2 macrophages into M1 macrophages within the TME. While passive targeted transport techniques allow drug-carrying nanomedicine to selectively accumulate in tumor regions, the efficacy is often hindered by the host's immune response and the inherent toxicity of certain nanomaterials. This review summarizes the current landscape of nanocarriers, emphasizing the need for future research to explore novel nanomaterials and expand the database of drug delivery systems to optimize therapeutic outcomes. Moreover, the potential of polarized macrophage-targeted therapies remains underexplored, suggesting a critical area for future breakthroughs.

Anti-inflammatory effects of cyclodextrin nanoparticles enable macrophage repolarization and reduce inflammation

Inflammation plays a critical role in the pathophysiology of many diseases, and dysregulation of the involved signaling cascades often culminates in uncontrollable disease progression and, ultimately, chronic manifestation. Addressing these disorders requires balancing inflammation control while preserving essential immune functions. Cyclodextrins (CDs), particularly β-CD, have gained attention as biocompatible biomaterials with intrinsic anti-inflammatory properties, and chemical modification of their backbone offers a promising strategy to enhance their physicochemical properties, adaptability, and therapeutic potential. This study evaluated and characterized the immunomodulatory effects of amphiphilic CD derivatives, which self-assemble into nanoparticles, compared to soluble parent β-CD. In a human macrophage model, CD nanoparticles demonstrated superior anti-inflammatory activity, with derivative-specific effects tied to their physicochemical properties, surpassing the soluble β-CD control. Alongside the downregulation of key pro-inflammatory markers, significant reductions in inflammasome activation and changes in lipid profiles were observed. The findings of this study underscore the potential of cyclodextrin-based nanoparticles as versatile biomaterials for treating the complex pathophysiology of various acute and chronic inflammation-associated disorders.

STING agonists and PI3Kγ inhibitor co-loaded ferric ion-punicalagin networks for comprehensive cancer therapy

Nanoparticles-based drug delivery system has been a promising approach for the treatment of colorectal cancer (CRC), which can be combined with chemotherapy, targeted therapy and immunotherapy to improve the treatment of CRC. 2′3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is an agonist of the STING signaling pathway activating antitumor immunity. IPI-549 is a small-molecule inhibitor for phosphatidylinositol 3-kinase γ (PI3Kγ), which can induce M1 macrophages polarization to provide pro-inflammatory microenvironment to suppress tumors. Here, we developed a ferric ion-punicalagin network (Fe-PU), which can be not only used as an inducer of ferroptosis, but also serve as a carrier to load cGAMP and IPI-549 to obtain nanohybrid (Fe-PU/CD-IPI). In order to improve the delivery effect and targeted ability to CRC, a cyclic arginine-glycine-aspartic acid peptide linked-bovine serum albumin were utilized to modify Fe-PU/CD-IPI to prepare nanohybrid Fe-PU/CD-IPI@cBSA. The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

Comparative study on physicochemical characterization and immunomodulatory activities of neutral and acidic Lycium barbarum polysaccharides

Lycium barbarum polysaccharides (LBPs) are recognized as key bioactive constituents of Lycium barbarum with diverse biological activities. However, current research on LBPs is largely confined to crude extracts, offering limited insight into the structural properties underlying their biological effects. In this study, we separated crude LBP into acidic LBP (ALBP) and neutral LBP (NLBP), which exhibited distinct physicochemical properties. ALBP, consisting of 76.18 % galacturonic acid (GalA), demonstrated crystallinity, thermal stability and gelatinous characteristics. In contrast, NLBP, with only 3.16 % GalA, displayed a more porous structure and superior fluidity. Furthermore, functional analysis revealed that NLBP exhibited enhanced immunoregulatory effects by activating dendritic cells and repolarizing macrophages. In a B16F10 melanoma-bearing C57BL/6 J mice model, NLBP significantly inhibited tumor growth with an inhibition rate of 66.7 % through macrophage repolarization. The findings highlight the distinct biological effects of NLBP and ALBP, providing a theoretical foundation for the refined utilization of LBP.

Orchestrated Copper-Loaded Nanoreactor for Simultaneous Induction of Cuproptosis and Immunotherapeutic Intervention in Colorectal Cancer

Ion interference, including intracellular copper (Cu) overload, disrupts cellular homeostasis, triggers mitochondrial dysfunction, and activates cell-specific death channels, highlighting its significant potential in cancer therapy. Nevertheless, the insufficient intracellular Cu ions transported by existing Cu ionophores, which are small molecules with short blood half-lives, inevitably hamper the effectiveness of cuproptosis. Herein, the ESCu@HM nanoreactor, self-assembled from the integration of H-MnO2 nanoparticles with the Cu ionophore elesclomol (ES) and Cu, was fabricated to facilitate cuproptosis and further induce relevant immune responses. Specifically, the systemic circulation and tumoral accumulation of Cu, causing irreversible cuproptosis, work in conjunction with Mn2+, resulting in the repolarization of tumor-associated macrophages (TAMs) and amplification of the activation of the cGAS-STING pathway by damaged DNA fragments in the nucleus and mitochondria. This further stimulates antitumor immunity and ultimately reprograms the tumor microenvironment (TME) to inhibit tumor growth. Overall, ESCu@HM as a nanoreactor for cuproptosis and immunotherapy, not only improves the dual antitumor mechanism of ES and provides potential optimization for its clinical application, but also paves the way for innovative strategies for cuproptosis-mediated colorectal cancer (CRC) treatment.

Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy.

Nerve-cancer crosstalk has gained substantial attention owing to its impact on tumour growth, metastasis and therapy resistance. Effective therapeutic strategies targeting tumour-associated nerves within the intricate tumour microenvironment remain a major challenge in pancreatic cancer. Here we develop Escherichia coli Nissle 1917-derived outer membrane vesicles conjugated with nerve-binding peptide NP41, loaded with the tropomyosin receptor kinase (Trk) inhibitor larotrectinib (Lar@NP-OMVs) for tumour-associated nerve targeting. Lar@NP-OMVs achieve efficient nerve intervention to diminish neurite growth by disrupting the neurotrophin/Trk signalling pathway. Moreover, OMV-mediated repolarization of M2-like tumour-associated macrophages to an M1-like phenotype results in nerve injury, further accentuating Lar@NP-OMV-induced nerve intervention to inhibit nerve-triggered proliferation and migration of pancreatic cancer cells and angiogenesis. Leveraging this strategy, Lar@NP-OMVs significantly reduce nerve infiltration and neurite growth promoted by gemcitabine within the tumour microenvironment, leading to augmented chemotherapy efficacy in pancreatic cancer. This study sheds light on a potential avenue for nerve-targeted therapeutic intervention for enhancing pancreatic cancer therapy.

Dual-targeted halofuginone hydrobromide nanocomplexes for promotion of macrophage repolarization and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes in adjuvant-induced arthritis in rats

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic inflammation and excessive proliferation of the synovium. Currently, treatment options focus on either reducing inflammation or inhibiting synovial hyperplasia. However, these modalities are unsatisfactory in achieving the desired therapeutic outcomes. Halofuginone hydrobromide (HF), an herbal active ingredient, has demonstrated pharmacological effects of both anti-inflammation and inhibition of synovial hyperplasia proliferation. However, HF’s medical efficacy is limited due to its poor water solubility, short half-life, and non-target toxicity. In the current study, by using the advantages of nanotechnology, we presented a novel dual-targeted nanocomplex, termed HA-M@P@HF NPs, which consisted of a hyaluronic acid (HA)-modified hybrid membrane (M)-camouflaged poly lactic-co-glycolic acid (PLGA) nanosystem for HF delivery. These nanocomplexes not only overcame the limitations of HF but also achieved simultaneous targeting of inflammatory macrophages and human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA). In vivo experiments demonstrated that these nanocomplexes effectively suppressed immune-mediated inflammation and synovial hyperplasia, safeguarding against bone destruction in rats with adjuvant-induced arthritis (AIA). Remarkable anti-arthritic effects of these nanocomplexes were accomplished through promoting repolarization of M1-to-M2 macrophages and apoptosis of HFLS-RA, thereby offering a promising therapeutic strategy for RA.

Chitosan-based self-healing thermosensitive hydrogel loaded with siHMGB1 for treatment of rheumatoid arthritis via macrophage repolarization

Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by immune cell activation, particularly macrophages. An imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages causes synovial inflammation and joint damage, worsening RA. This study presents a biomacromolecular hydrogel delivery system with apoferritin nanoparticles for effective delivery of small interfering high mobility group protein (siHMGB1). The system was designed to promote the polarization of M1 macrophages to the M2 phenotype by downregulating the HMGB1/TLR4/NF-κB-p65 signaling pathway, offering a potential therapeutic approach for the treatment of RA. The oxidized chondroitin sulfate - chitosan - sodium glycerol β - phosphate - Fn/siHMGB1 (OCF/siHMGB1) hydrogel system possessed temperature-sensitive and self-healing properties, enabling the sustained, stable, and efficient release of siHMGB1 at the affected joint. After effective uptake by macrophages, siHMGB1 could effectively repolarize M1-phenotype macrophages to M2-phenotype via the HMGB1/TLR4/NF-κB-p65 signaling pathway both in vitro and in vivo. Additionally, it suppressed the release of pro-inflammatory cytokines and upregulated anti-inflammatory cytokines, which significantly blocked the TLR4/p65-mediated inflammatory signaling. In conclusion, the siHMGB1-loaded hydrogel delivery system designed in this study is effective in treating RA and highlights the potential of gene therapy to induce repolarization of M1 to M2 macrophages for RA treatment.