Synergistic Therapy Research Articles

De novo strategy of organic semiconducting polymer brushes for NIR-II light-triggered carbon monoxide release to boost deep-tissue cancer phototheranostics.

The integration of photoacoustic imaging (PAI) and photothermal therapy (PTT) within the second near-infrared (NIR-II) window, offering a combination of high-resolution imaging and precise non-invasive thermal ablation, presents an attractive opportunity for cancer treatment. Despite the significant promise, the development of this noninvasive phototheranostic nanomedicines encounters challenges that stem from tumor thermotolerance and limited therapeutic efficacy. In this contribution, we designed an amphiphilic semiconducting polymer brush (SPB) featuring a thermosensitive carbon monoxide (CO) donor (TDF-CO) for NIR-II PAI-assisted gas-augmented deep-tissue tumor PTT. TDF-CO nanoparticles (NPs) exhibited a powerful photothermal conversion efficiency (43.1%) and the capacity to trigger CO release after NIR-II photoirradiation. Notably, the liberated CO not only acts on mitochondria, leading to mitochondrial dysfunction and promoting cellular apoptosis but also hinders the overexpression of heat shock proteins (HSPs), enhancing the tumor's thermosensitivity to PTT. This dual action accelerates cellular thermal ablation, achieving a gas-augmented synergistic therapeutic effect in cancer treatment. Intravenous administration of TDF-CO NPs in 4T1 tumor-bearing mice demonstrated bright PAI signals and remarkable tumor ablation under 1064nm laser irradiation, underscoring the potential of CO-mediated photothermal/gas synergistic therapy. We envision this tailor-made multifunctional NIR-II light-triggered SPB provides a feasible approach to amplify the performance of PTT for advancing future cancer phototheranostics.

Nanoplatform-based synergistic cancer Immuno-Chemodynamic therapy.

Immunotherapy has made excellent breakthroughs in the field of cancer treatments, but faces challenges with low immunogenicity of tumor cells and an immunosuppressive tumor microenvironment (ITME). The emerging chemodynamic therapy (CDT) based on the Fenton/Fenton-like reaction can induce immunogenic cell death (ICD) to enhance tumor immunogenicity, facilitating the transition from immune-cold to immune-hot tumors. Synergistic CDT and immunotherapy based on advanced nanotechnology have shown immense promise for improving therapeutic efficacy while minimizing side effects in cancer treatment. This review summarizes and discusses recent advances in the field, with the goal of designing a high-quality nanoplatform to enhance synergistic CDT in combination with immunotherapy and lay the foundation for its future clinical translation.

Fe/Cu Bimetallic Nanozyme Co-Assembled with 177Lu and Tanshinone for Quadruple-Synergistic Tumor-Specific Therapy.

The co-loading of radionuclides and small-molecule chemotherapeutic drugs as nanotheranostic platforms using nanozymes holds tremendous potential for imaging-guided synergistic therapy. This study presents such nanotheranostic platform (177Lu-MFeCu@Tan) via co-assembling 177Lu radionuclide and tanshinone (Tan) into Fe/Cu dual-metal nanozyme (MFeCu). This platform simultaneously enables single-photon emission computed tomography (SPECT) imaging and a quadruple-synergistic tumor therapy approach, including internal radioisotope therapy (RIT), catalysis therapy, chemotherapy, and MFeCu-mediated ferroptosis and cuproptosis therapy. In this platform, the MFeCu can catalyze excessive intracellular hydrogen peroxide (H2O2) to generate radical oxygen species (ROS) and deplete glutathione (GSH). The excess of H2O2 and GSH are main factors for radioresistance and chemoresistance, reducing them can enhance chemotherapy and RIT. The generated ROS and depleted GSH further induce mitochondrial dysfunction and promote the aggregation of lipoylated dihydrolipoamide S-acetyltransferase and lipid peroxidation, causing the enhance of ferroptosis and cuproptosis. The in vitro and in vivo results demonstrate that this quadruple-synergistic approach shows significant therapeutic efficacy to complete tumor eradication and reduced recurrence in vivo. In conclusion, this work presents a promising strategy for designing SPECT imaging-guided quadruple-synergistic therapy and highlights the feasibility of developing a self-assembled radionuclide and small molecule chemotherapy drugs nanotherapeutic platform for combined treatment of cancer.

PH-responsive AIE nanogels for synergistic chemo-photodynamic cancer therapy with imaging guidance

Abstract Photodynamic therapy (PDT) is a promising cancer treatment that uses photosensitizers (PSs) to generate cytotoxic reactive oxygen species (ROS) under light, but improving its efficacy is crucial for clinical applications. To address this, we propose a smart nanoplatform (P@BAO-DOX) for synergistic chemo-photodynamic therapy, featuring efficient PDT, controllable drug release, and fluorescence imaging guidance. We designed an aggregation-induced emission (AIE)-based PS (BAO) with effective ROS generation and NIR-II fluorescence. Additionally, BAO as a PS and doxorubicin (DOX) as a chemo drug were encapsulated in pH-responsive nanogels (PNA) to obtain P@BAO-DOX nanogels. Upon uptake by tumor cells, the nanogel releases drugs in acidic conditions, leading to cell death. White light irradiation further triggers BAO to produce substantial ROS, enhancing phototoxicity and synergistic chemo-PDT cancer therapy. Thus, P@BAO-DOX nanogels, as a smart nanoplatform, offer precise drug release and efficient ROS generation for imaging-guided chemo-PDT synergistic therapy, showing promise in advancing cancer treatment.

TMIC-85. THE MECHANISM OF COMBINED HYDROGEN-CHEMICAL THERAPY BASED ON ACTIVE MAGNESIUM MICROMOTORS FOR INHIBITING GLIOBLASTOMA RECURRENCE BY MODULATING TUMOR MICROENVIRONMENT

Abstract OBJECTIVE This study aims to develop an innovative therapeutic strategy to prevent postoperative recurrence of Glioblastoma (GBM), a condition with poor prognosis and high recurrence rates. The focus is on exploring the efficacy of synergistic hydrogen-chemical therapy in inhibiting GBM recurrence, especially by reducing surgery-induced inflammation and enhancing the sensitivity of GBM cells to chemotherapy. METHODS The study employed the fabrication of Mg-Motor-DOX using a biodegradable polylactic acid-glycolic acid copolymer (PLGA) and gelatin containing Doxorubicin (DOX). The reaction of Mg with water produces hydrogen (H2), which aids in scavenging reactive oxygen species (ROS) and inflammation, alongside the specific release of chemotherapy drugs at the tumor site. A thermosensitive hydrogel was developed for in situ delivery of Mg-Motor-DOX to the tumor residual cavity. Additionally, RNA sequencing was used to study the transcriptional changes in the GBM tumor microenvironment (TME) induced by this therapy. RESULTS The study presents initial evidence of the in vivo efficacy of synergistic hydrogen-chemical therapy against GBM. The Mg-Motor-DOX mediated therapy not only scavenged ROS and reduced inflammation but also specifically released chemotherapy drugs at the tumor site, enhancing their effectiveness. RNA-Seq technology elucidated the molecular mechanisms underlying the therapy’s efficacy, revealing significant transcriptional changes in the GBM TME. CONCLUSION Synergistic hydrogen-chemical therapy, facilitated by Mg-Motor-DOX, shows promising potential in preventing the postoperative recurrence of GBM. This innovative approach effectively combines anti-inflammatory benefits and enhanced chemosensitivity, offering new strategies for GBM treatment. The molecular insights provided by RNA-Seq technology contribute to a deeper understanding of tumor treatment mechanisms, paving the way for future clinical applications.

Ultrasound-Responsive Lipid Nanoplatform with Nitric Oxide and Carbon Monoxide Release for Cancer Sono-Gaso-Therapy.

Local gas therapy is emerging as a potential cancer treatment approach due to its specificity as gas-containing molecules can be packed into a nanodelivery system to release the corresponding gaseous molecules around the tumor site upon a suitable stimulus. Single-gas therapy has been reported, while synergistic dual-gas therapy has rarely been reported. Herein, we report a dual-gas-containing nanoplatform for synergistic cancer gasotherapy upon ultrasound irradiation. First, a robust ultrasound-responsive lipid-coated nanosystem was prepared with suitable particle size and characteristics. A low-intensity ultrasound (1.25 W/cm2) was found to simultaneously modulate carbon monoxide (CO) and nitric oxide (NO) release from the nanosystem in media and CT26 colon cancer cells for efficient therapeutic effect. The intracellular release promoted the overgeneration of reactive oxygen species (ROS) and triggered cancer cell apoptosis synergistically. The in vivo test demonstrated that the optimal dual-gas-containing formulation efficiently inhibited tumor growth (by ∼87%) at relatively low doses upon ultrasound irradiation (1.25 W/cm2, 5 min). This therapeutic efficacy shows that the current responsive lipid-coated delivery system has potential for ultrasound-triggered dual-gas therapy of both superficially and deeply seated cancers.

Switchable ROS generator and scavenger to prevent the cisplatin induced acute kidney injury and improve efficacy via synergistic chemodynamic/immune therapy

Acute kidney injury (AKI) induced by cisplatin (DDP), which is accompanied with the generation of reactive oxygen species (ROS), is a severe side effect during treatment and restricts the application of DDP. In this study, we develop ultrasmall Mn3O4 nanozyme (UMON) with tumor microenvironment (TME) responsive ROS scavenging and generating as adjuvant to alleviate DDP induced AKI with improved efficacy. In kidney, UMON with superoxide dismutase and catalase activity acts as ROS scavenger to eliminate ROS generated by DDP, successfully protecting the renal cells/tissue and alleviating AKI during DDP treatment. Alternatively, UMON rapidly responses to the high GSH level in TME and release Mn2+ in tumor. This unique feature endows it to generate hydroxyl radicals (∙OH) through a Fenton-like reaction and deplete GSH in tumor cell and tissue, achieving high efficient chemodynamic therapy (CDT). More importantly, the Mn2+ successfully activates the cGAS-STING pathway, initiating the immune response and effectively inhibiting the tumor metastases. The synergistic CDT and immune therapy effectively improve the anti-tumor efficacy of DDP in vitro and in vivo. This study demonstrates that TME responsive ROS scavenger/generator shows the potential to reduce side effects of DDP while improve its therapeutic efficacy, providing a new avenue to achieve efficient chemotherapy and promoting the progress of clinical chemotherapy.

Capturing Hydrophilic Chemotherapeutics Agents Into siRNA-Encapsulated Vesicle-Like Nanoparticles for Convenient ICB-Chemo Combination Therapy.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

An alternative way to break the matrix barrier: an experimental study of a LIFU-mediated, visualizable targeted nanoparticle synergistic amplification for the treatment of malignant fibroblasts

Malignant fibroblasts (MFs) are widely present in various diseases and are characterized by connective tissue proliferation; these cells act as a physical barrier that severely limits drug delivery and affects disease outcomes. Based on this, we constructed the smart, integrated, theranostic, targeted lipid nanoprobe HMME-RG3@PFH to overcome the bottleneck in the early diagnosis and treatment of MF-related diseases. The protein glucose transporter protein 1 (GLUT-1) is overexpressed on MFs, and its ideal substrate, ginsenoside RG3 (RG3), significantly enhances the targeted uptake of HMME-RG3@PFH by MFs in a hypoxic environment and endows the nanomaterial with stealthiness to prolong its circulation. Perfluorohexane (PFH), a substance that can undergo phase change, was encapsulated in the lipid core and vaporized for ultrasound-enhanced imaging under low-intensity focused ultrasound (LIFU) irradiation. Moreover, hematoporphyrin monomethyl ether (HMME) was loaded into the lipid bilayer for photoacoustic molecular imaging and sonodynamic therapy (SDT) of MFs under the combined effects of LIFU. Additionally, HMME-RG3@PFH instantaneously burst during visualization to promote targeted drug delivery. In addition, the increased number of exposed RG3 fragments can regulate the MFs to enter a quiescent state. Overall, this nanoplatform ultimately achieves dual-modal imaging with targeted and precise drug release for visualization and synergistic amplification therapy, providing a new possibility for the early diagnosis and precise treatment of MF-related diseases.

Blazing Carbon Dots: Unfolding its Luminescence Mechanism to Photoinduced Biomedical Applications.

Carbon dots (CDs) are carbon-based nanomaterials that have garnered immense interest due to their exceptional photophysical and optoelectronic properties. They have been employed extensively for biomedical imaging and phototherapy due to their superb water dispersibility, low toxicity, outstanding biocompatibility, and exceptional tissue permeability. This review summarizes the luminescence mechanism of CDs. The modification in CDs via various doping routes is comprehensively reviewed, and the effect of such alterations on their photophysical properties, such as photoluminescence (PL), absorbance, and reactive oxygen species generation ability, is also highlighted. This review also aims to summarize the role of CDs in cellular imaging and fluorescence lifetime imaging for cellular metabolism. Subsequently, recent advancements and the future prospects of CDs as nanotheranostic agents have been discussed. Herein, we have discussed the role of CDs in photothermal, photodynamic, and synergistic therapy of anticancer, antiviral, and antibacterial applications. The overall summary of the review highlights the future prospects of CD-based research in bioimaging and biomedicine.

Wide‐Spectrum Nano‐Antibiotics Based on TPA‐Py@AuNCs⊂BSA for Multimodal Synergistic Therapy of Drug‐Resistant Bacteria and Wound Infections

ABSTRACTTo meet the high requirements of biomedical applications in antimicrobial agents, it is crucial to explore efficient nano‐antimicrobial agents with no resistance and good biocompatibility for treating infected wounds. In this study, composite nano‐antibiotic TPA‐Py@AuNCs⊂BSA nanoparticles (TAB NPs) are prepared using hollow mesoporous Au nanocages (AuNCs) loaded with a photosensitizer (namely TPA‐Py) with D‐π‐A structure showing aggregation‐induced emission properties. When TPA‐Py is encapsulated in the cavity of AuNCs, its fluorescence is suppressed. In the presence of photothermal induction, TPA‐Py can be released from the AuNCs, allowing for the restoration of fluorescence illumination and the specific imaging of Gram‐positive bacteria. TAB NPs demonstrate outstanding antimicrobial activity against a variety of bacteria, and this multimodal antimicrobial property does not lead to the development of bacterial resistance. In vitro experiments show that TAB NPs could eliminate bacteria and ablate bacterial biofilm. In vivo experiments show that the synergistic antimicrobial effect of TAB NPs has a significant positive impact on the treatment of infected wounds, including rapid antibacterial action, promotion of M2 macrophage polarization, and enhancement of chronic wound healing. This study provides an effective strategy for developing wide‐spectrum nano‐antibiotics for the ablation of bacterial biofilms and the treatment of infected wounds.

Inhibition of Aβ Aggregation and Tau Phosphorylation with Functionalized Biomimetic Nanoparticles for Synergic Alzheimer's Disease Therapy.

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because of the poor brain bioavailability of drugs, which is attributed to the blood-brain barrier (BBB) restriction and complicated brain conditions. Herein, HM-DK was proposed for synergistic therapy of AD by using hollow mesoporous manganese dioxide (HM) as a carrier to deliver an Aβ-inhibiting peptide and a Dp-peptide inhibitor of Tau-related fibril formation synergistically. Inspired by 4T1 cancer cells promoting BBB penetration during brain metastasis, a prospective biomimetic nanocarrier (HM-DK@CM) encapsulated by 4T1 cell membranes was designed. After crossing the BBB, HM-DK@CM inhibited Aβ aggregation and prevented Tau phosphorylation simultaneously. Moreover, by taking advantage of the catalase-like activity of HM, HM-DK@CM relieved oxidative stress and altered the microenvironment associated with the development of AD. Compared with the single therapeutic drug, HM-DK@CM restored nerve damage and improved AD mice's learning and memory abilities by decreasing Aβ oligomer, p-Tau protein, and inflammation through various pathways for synergistic therapy, which has broad prospects for the effective treatment of AD.

Manganese-doped liquid metal nanoplatforms for cellular uptake and glutathione depletion-enhanced photothermal and chemodynamic combination tumor therapy

Chemodynamic therapy (CDT) involves the catalysis of in situ overexpressed hydrogen peroxide (H2O2) into highly toxic reactive oxygen species (ROS) to treat tumors. However, the efficacy of CDT is greatly hampered by limited cellular internalization efficiency, ROS scavenging by glutathione (GSH), and slow reaction rate. To overcome the current limitations of CDT, a manganese-doped and polyethylene glycol (PEG)-modified liquid metal (LM)-silica nanoplatform (labeled as Mn-LMOP) with varying stiffness is constructed to achieve synergistic photothermal therapy (PTT) and CDT, which can further induce immunogenic cell death (ICD) in tumors to enhance the anti-tumour effects. Significantly, benefiting from the increased stiffness, the Mn-LMOP nanoparticles (NPs) can enhance cellular uptake and lysosomal escape, and gradually accumulate in tumor sites. Moreover, manganese-doped NPs exhibite good photothermal effects and can rapidly reacte with intratumoral GSH to produce Mn2+, inhibiting GSH-mediated ROS clearance and promoting the efficiency of CDT. This combined treatment strategy can activate the immune response of the tumors, which holds the promise of photothermal/chemodynamic/immune multimodal therapeutic effects. This LM-based nanosystem will provide a paradigm for enhanced CDT/PTT combination anti-tumour efficacy. Statement of significanceChemodynamic therapy (CDT) is a promising drug-free treatment approach characterized by its low invasiveness and minimal side effect. However, CDT encounters challenges such as high levels of glutathione (GSH), low Fenton-like reaction rate, and inefficient cellular uptake in tumor tissues. Here, a manganese-doped liquid metal (LM) nanomaterial was designed to achieve synergistic photothermal therapy (PTT) and CDT. This innovative strategy enhanced cellular uptake by adjusting the mechanical property of nanoparticles (NPs) and facilitated the consumption of GSH, while simultaneously accelerating the Fenton-like reaction rate with the assistance of PTT-mediated hyperthermia. This combined CDT/PTT strategy also activated the immune response within the tumor, demonstrating significant therapeutic potential.

Metal-Phenolic Networks: A Promising Frontier in Cancer Theranostics.

The burgeoning field of cancer theranostics has been significantly advanced by the development of Metal-Phenolic Networks (MPNs), a new class of supramolecular architectures that integrate the advantages of metals and polyphenols. This review focuses on MPNs and their promising applications in cancer theranostics. Through a systematic literature search spanning from 2010 to 2023 in databases including PubMed, Scopus, and Web of Science. The period of search was justified by the rapid evolution of nanomaterials in cancer therapy, with MPNs emerging as a significant player in biomedical applications within the specified timeframe. This review discusses the classification and structure of polyphenolic compounds, as well as their mechanisms of action in cancer treatment. The applications of MPNs in chemotherapy drug delivery, photothermal therapy, chemodynamic therapy, biomedical imaging, and synergistic therapy are especially detailed. The authors emphasize the significance of MPNs in cancer nanomedicine and look forward to their future development directions.

An injectable dual-layer chitosan-alginate nano-hydrogel incorporated Cu(I)-isopolymolybdate-based metal-organic framework tailored for three-in-one anti-cancer nanotherapy

Designing potential agents and constructing hydrophilic nano-hydrogel platforms for biomedical and pharmaceutical applications, especially for polyoxometalate-based metal-organic frameworks (PMOF), present both great desirability and significant challenges. A unique open porous Cu(I)-isopolymolybdate-based metal-organic framework (CCUT) has been self-assembled through ionothermal processes for in vivo synergistic anti-cancer therapy. The periodicity of Drugs@CCUT-1 (nano-crystals of CCUT after cation exchange and anti-cancer drugs upload) has been investigated by synchrotron wide-angle X-ray scattering, confirming the lattice structure unchanged. To mitigate toxicity, enhance stimuli-responsive drug delivery, hydrophilicity, and biocompatibility, an injectable dual-layer chitosan//alginate-based nano-hydrogel is developed to incorporate Drugs@CCUT-1. Potential interactions between the chitosan layer and the surface of CCUT-1 have been analyzed by Density Functional Theory (DFT). Furthermore, the nanoparticles Drugs@CCUT-1@Gel exhibit efficient type I photodynamic therapy (PDT) and chemodynamic therapy (CDT) within the bio-window, effectively eradicating tumors in deep tissue. CCUT-1 generates a substantial amount of reactive oxygen species (ROS), stimulating the Keap1-Nrf2 signaling pathway and resulting in the expression of phase II enzymes, typically HO-1. CCUT-1@Gel not only demonstrates high capacity for anti-cancer drug upload and release, but also exhibits strong synergistic CDT/PDT in vivo anti-tumor efficacy. Hence, CCUT-1@Gel represents a promising in vivo nano-platform for synergistic chemotherapy (CT)/CDT/PDT three-in-one anti-cancer approach.

Controllable morphology CoFe2O4/g-C3N4 pH-responsive nanoplatform for enhanced chemo-photodynamic synergistic cancer therapy

Controllable morphology CoFe2O4/g-C3N4 pH-responsive nanoplatform for enhanced chemo-photodynamic synergistic cancer therapy

Augment of Ferroptosis with Photothermal Enhanced Fenton Reaction and Glutathione Inhibition for Tumor Synergistic Nano-Catalytic Therapy

Augment of Ferroptosis with Photothermal Enhanced Fenton Reaction and Glutathione Inhibition for Tumor Synergistic Nano-Catalytic Therapy

Ultrasound/Magnetic Resonance Bimodal Imaging-Guided CD20-Targeted Multifunctional Nanoplatform for Photothermal/Chemo Synergistic Therapy of B-Cell Lymphoma

Ultrasound/Magnetic Resonance Bimodal Imaging-Guided CD20-Targeted Multifunctional Nanoplatform for Photothermal/Chemo Synergistic Therapy of B-Cell Lymphoma

Reactive oxygen species augmented polydopamine-chlorin e6 nanosystem for enhanced chemo/photothermal/photodynamic therapy: A synergistic trimodal combination approach in vitro & in vivo

Amalgamation of near-infrared laser phototherapies with chemotherapy in multi-modal synergistic therapy holds great promise for future precision cancer nanomedicine due to its minimal invasiveness, reduced adverse reactions, and high anticancer efficacy. Herein, CuO nanoparticles were functionalized with photosensitizer molecule, chlorin e6 (Ce6) and coated with polydopamine (PDA) to achieve a drug delivery system (CuO@Ce6-PDA) with photothermal/photodynamic therapy (PTT/PDT). Subsequently, chemical drug PTX was loaded for chemotherapy, and folic acid (FA) serving as cancer-targeting exterior material. Prepared FA@CuO@Ce6-PDA/PTX nanoparticles were nano-sized with favorable biocompatibility, colloidal stability, optimal surface charge, effective PTX loading, and controllable PTX release. In vitro studies on 4 T1 cells showed that FA@CuO@Ce6-PDA/PTX had noteworthy synergistic therapeutic antitumour effects featuring chemo/PTT/PDT with IC50 of 50 μg/mL lower than that FA@CuO@Ce6-PDA/PTX without NIR laser irradiation (225 μg/mL). Additionally, FA@CuO@Ce6-PDA/PTX produced intracellular high reactive oxygen species (ROS) in presence of 660 nm laser, altering mitochondrial membrane potential and promoting tumour cell death. In vivo results indicate nanoplatform could accumulate in tumour spots enabling thermal imaging capabilities and exhibit synergistic therapeutic effect if irradiated with NIR laser (808 and 660 nm), evident from in vitro antitumour assay. Therefore, in vitro finding postulates FA@CuO@Ce6-PDA/PTX could be an intriguing nanoplatform for Chemo/PTT/PDT-based combination therapy.

Enhancing Chemoimmunotherapy for Colorectal Cancer with Paclitaxel and Alantolactone via CD44-Targeted Nanoparticles: A STAT3 Signaling Pathway Modulation Approach

Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found to augment the anticancer efficacy of paclitaxel (P) at a molar ratio of 1:0.5 (P:A) through induction of more potent ICD via modulation of STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve tumor targeting ability and bioavailability of hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) was chemically modified with paclitaxel (PTX) and hyaluronic acid (HA) as a backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed for co-delivery of A and P in colorectal cancer treatment, aiming to achieve synergistic toxicity-based chemo-immunotherapy. The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting, providing a solid foundation for subsequent synergistic therapy and immunoregulation. In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation, thus offering a novel approach for colorectal cancer chemoimmunotherapy.