Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

Hierarchically Targeted and Penetrated Delivery of Drugs to Tumors by Size‐Changeable Graphene Quantum Dot Nanoaircrafts for Photolytic Therapy

Theranostic nanohybrids are promising for effective delivery of therapeutic drug or energy and for imaging‐guided therapy of tumors, which is demanded in personalized medicine. Here, a size‐changeable graphene quantum dot (GQD) nanoaircraft (SCNA) that serves as a hierarchical tumor‐targeting agent with high cargo payload is developed to penetrate and deliver anticancer drug into deep tumors. The nanoaircraft is composed of ultrasmall GQDs (less than 5 nm) functionalized with a pH‐sensitive polymer that demonstrates an aggregation transition at weak acidity of tumor environment but is stable at physiological pH with stealth function. A size conversion of the SCNA at the tumor site is further actuated by near‐infrared irradiation, which disassembles 150 nm of SCNA into 5 nm of doxorubicin (DOX)/GQD like a bomb‐loaded jet, facilitating the penetration into the deep tumor tissue. At the tumor, the penetrated DOX/GQD can infect neighboring cancer cells for repeated cell killing. Such a SCNA integrated with combinational therapy successfully suppresses xenograft tumors in 18 d without distal harm. The sophisticated strategy displays the hierarchically targeted and penetrated delivery of drugs and energy to deep tumor and shows potential for use in other tumor therapy.     

Drug-Eluting Shear-Thinning Hydrogel for the Delivery of Chemo- and Immunotherapeutic Agents for the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a malignant and deadly form of liver cancer with limited treatment options. Transcatheter arterial chemoembolization, a procedure that delivers embolic and chemotherapeutic agents through blood vessels, is a promising cancer treatment strategy. However, it still faces limitations, such as inefficient agent delivery and the inability to address tumor-induced immunosuppression. Here, a drug-eluting shear-thinning hydrogel (DESTH) loaded with chemotherapeutic and immunotherapeutic agents in nanocomposite hydrogels composed of gelatin and nanoclays is presented as a therapeutic strategy for a catheter-based endovascular anticancer approach. DESTH is manually deliverable using a conventional needle and catheter. In addition, drug release studies show a sustained and pH-dependent co-delivery of the chemotherapy doxorubicin (acidic pH) and the immune-checkpoint inhibitor aPD-1 (neutral pH). In a mouse liver tumor model, the DESTH-based chemo/immunotherapy combination has the highest survival rate and smallest residual tumor size. Finally, immunofluorescence analysis confirms that DESTH application enhances cell death and increases intratumoral infiltration of cytotoxic T-cells. In conclusion, the results show that DESTH, which enables efficient ischemic tumor cell death and effective co-delivery of chemo- and immunotherapeutic agents, may have the potential to be an effective therapeutic modality in the treatment of HCC.     

Emerging Approaches of Cell‐Based Nanosystems to Target Cancer Metastasis

Cancer metastasis accounts for the high mortality of cancer‐related deaths and the therapy is greatly challenged by the limited drug delivery efficiency. Inspired by the essential role of culprit cancer cells and versatile accessory cells during cancer metastasis, diverse cell‐based nanosystems (CBNs) are emerging as attractive and encouraging drug delivery platforms to target cancer metastasis. Herein, the authors focus on the emerging strategies of versatile CBNs that synergistically combine the merit of source cells and nanoparticles for antimetastasis therapy. CBNs are usually comprised of natural nanosized vesicles, cell membrane camouflaged nanoparticles, and bioengineered living cell vehicles. The authors discuss the rationality and advances of various CBNs in targeting different stages of cancer metastasis, including primary tumor, circulating tumor cells (CTCs), and distant metastasis as well as the tumor immune microenvironments (TIM). On this basis, this review provides some feasible perspectives on designing CBNs to enhance the drug delivery efficiency for treating cancer metastasis.     

A Multistage-Responsive Antibody-Delivery Strategy to Improve Immunotherapy for NSCLC Brain Metastasis by Ultrasensitive Releasing and Tumor-Anchoring

Immune checkpoint blockade (ICB) therapy has emerged as a promising approach in clinical oncology. For brain metastases, the presence of the robust blood–brain barrier (BBB) and potential immune-related adverse events (irAEs) pose significant challenges. Here, a multistage-responsive antibody-delivery strategy is developed for non-small cell lung cancer (NSCLC) brain metastases, with the ultra-pH sensitivity borate bonds. The antibody-delivery nanoformulation (MB-aPDL1) is able to maintain the “silent state” in health tissue, cross the BBB/BTB by the GLUT1-mediated transcytosis, release the functionalized aPDL1 responsively, and promote the aPDL1 tumor-anchoring. In the in vivo tumor region, the MB-aPDL1 rapidly releases the activated BPA₆-aPDL1, which successfully anchors to the tumor cells and improves the efficiency of ICB therapy. The two in vivo ICB therapy studies show a significant tumor growth inhibition from the MB-aPDL1 with an encouraging cure rate of 20% for the NSCLC brain metastases, due to enhanced immune response in tumor, commendably with less behavioral adverse reactions and liver damage. Taken together, this antibody-delivery strategy holds substantial potential for application in clinical treatment of brain metastases.     

Tumor-Activated Photosensitization and Size Transformation of Nanodrugs

Effective intratumoral distribution of anticancer agents with good tumor penetration is of practical importance for photo-chemotherapy. Herein, a metal-organic framework (MOF) assisted strategy is reported for smart delivery of aggregation-induced emission photosensitizer (AIE PS) and chemodrug for deep tumor penetration to realize effective image-guided photo-chemotherapy. A newly designed AIE PS is loaded inside an iron(III) carboxylate-based MOF, MIL-100, to produce PS@MIL-100, which is encapsulated by doxorubicin (Dox) conjugated poly(ethylene glycol) methyl ether (PEG) to yield Dox-PEG-PS@MIL nanoparticles (NPs) with a diameter of 120 nm. After Dox-PEG-PS@MIL NPs reached the tumor site, intratumoral H₂O₂ can cause the release of the loaded PS at the tumor surface for activatable photodynamic therapy (PDT). The Dox-PEG segment is simultaneously triggered to self-assemble into ultrasmall Dox NPs. Under light irradiation, PDT is activated at the tumor surface, synergistically enhancing the tumor penetration of Dox NPs along with their ultrasmall size. After endocytosis of Dox NPs, free Dox is released from Dox NPs under low pH to enter cell nuclei for effective chemotherapy. Accompanied by bright far-red/near-infrared emission from the PS, image-guided photo-chemotherapy with enhanced efficacy is achieved.     

Ferroptosis and Pyroptosis Co-Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.     

Pathogen‐Mimicking MnO Nanoparticles for Selective Activation of the TLR9 Pathway and Imaging of Cancer Cells

Here, design of the first pathogen‐mimicking metal oxide nanoparticles with the ability to enter cancer cells and to selectively target and activate the TLR9 pathway, and with optical and MR imaging capabilities, is reported. The immobilization of ssDNA (CpG ODN 2006) on MnO nanoparticles is performed via the phosphoramidite route using a multifunctional polymer. The multifunctional polymer used for the nanoparticle surface modification not only affords a protective organic biocompatible shell but also provides an efficient and convenient means for loading immunostimulatory oligonucleotides. Since fluorescent molecules are amenable to photodetection, a chromophore (Rhodamine) is introduced into the polymer chain to trace the nanoparticles in Caki‐1 (human kidney cancer) cells. The ssDNA coupled nanoparticles are used to target Toll‐like receptors 9 (TLR9) receptors inside the cells and to activate the classical TLR cascade. The presence of TLR9 is demonstrated independently in the Caki‐1 cell line by western blotting and immunostaining techniques. The magnetic properties of the MnO core make functionalized MnO nanoparticles potential diagnostic agents for magnetic resonance imaging (MRI) thereby enabling multimodal detection by a combination of MR and optical imaging methods. The trimodal nanoparticles allow the imaging of cellular trafficking by different means and simultaneously are an effective drug carrier system.     

Intratumoral Thermal Reading During Photo‐Thermal Therapy by Multifunctional Fluorescent Nanoparticles

The tremendous development of nanotechnology is bringing us closer to the dream of clinical application of nanoparticles in photothermal therapies of tumors. This requires the use of specific nanoparticles that must be highly biocompatible, efficient light‐to‐heat converters and fluorescent markers. Temperature reading by the heating nanoparticles during therapy appears of paramount importance to keep at a minimum the collateral damage that could arise from undesirable excessive heating. In this work, this thermally controlled therapy is possible by using Nd³⁺ ion‐doped LaF₃ nanocrystals. Because of the particular optical features of Nd³⁺ ions at high doping concentrations, these nanoparticles are capable of in vivo photothermal heating, fluorescent tumor localization and intratumoral thermal sensing. The successful photothermal therapy experiments here presented highlight the importance of controlling therapy parameters based on intratumoral temperature measurements instead of on the traditionally used skin temperature measurements. In fact, significant differences between intratumoral and skin temperatures do exist and could lead to the appearance of excessive collateral damage. These results open a new avenue for the real application of nano­particle‐based photothermal therapy at clinical level.     

Transient interferometric mapping of carrier plasma during external transient latch-up phenomena in latch-up test structures and I/O cells processed in CMOS technology

Substrate current distribution as trigger for external latch-up (LU) and transient latch-up (TLU) is analyzed by optical transient interferometric mapping (TIM) technique. The transient free carrier (plasma) concentration related to substrate current flow is studied for various guard-ring configurations and injection carrier type on special test structures and real I/O cells. TIM uncovers proximity effects in I/O cells causing substrate current crowding which are important for the definition of effective LU protection concepts.     

A Microenvironment Dual-Responsive Nano-Drug Equipped with PD-L1 Blocking Peptide Triggers Immunogenic Pyroptosis for Prostate Cancer Self-Synergistic Immunotherapy

Induction of immunogenic cell death (ICD) in tumor combined with immune checkpoint blockade (ICB) therapy is widely developed to improve the efficacy of cancer immunotherapy. However, the current ICD induced based on apoptosis, i.e., immunogenic apoptosis, is often restricted in immunogenicity owing to the inflammatory quenching that occurs early in apoptosis. Recently, pyroptosis is demonstrated to be a more efficient ICD form, i.e., immunogenic pyroptosis. The cell contents released during pyroptosis can powerfully activate tumor immunogenicity. Herein, first, it is demonstrated that lower doses of epigenetic drug decitabine can increase GSDME expression in prostate cancer (PCa) RM-1 cells and successfully induce an apoptosis-pyroptosis transition after photodynamic therapy (PDT). Subsequently, a microenvironment dual-responsive nano-drug equipped with PD-L1 blocking peptide (TSD@LSN-D) is developed for self-synergistic cancer immunotherapy. The poorly immunogenic RM-1 PCa model confirm that the powerful antitumor immune response evoked by TSD@LSN-D not only can effectively inhibit the primary tumor but also form a long-term immune memory to prevent PCa recurrence and metastasis. To the best of authors’ knowledge, this work presents the first concept that promotes the apoptosis–pyroptosis transition after tumor PDT through epigenetic modulation. Furthermore, the powerful combination of immunogenic pyroptosis with ICB opens a new platform for PCa immunotherapy.     

Amplifying Nanoparticle Targeting Performance to Tumor via Diels–Alder Cycloaddition

Traditional targeting approach utilizing biological ligands has to face the problems of limited receptors and tumor heterogeneity. Herein, a two‐step tumor‐targeting and therapy strategy based on inverse electron‐demand [4+2] Diels–Alder cycloaddition (iEDDA) is described. Owing to the unique acidic tumor microenvironment, an intravenous injection of tetrazine modified pH (low) insertion peptide could efficiently target and incorporate onto various cell surfaces in tumor tissue, such as cancer cells, vascular endothelial cells, and tumor‐associated fibroblasts. The “receptor‐like” tetrazine groups with a large amount and homogeneous intratumoral distribution could then serve as the baits to greatly amplify the tumor‐targeting ability of indocyanine green (ICG)‐loaded and trans‐cyclooctene (TCO)‐conjugated human serum albumin (HSA) nanoparticles (TCO‐HSA‐ICG NPs) via iEDDA after the second intravenous injection. Compared with the passive enhanced permeability and retention (EPR) effect and traditional active targeting approaches, the targeting performance and photothermal therapeutic effect based on the two‐step strategy are significantly enhanced, while no notable toxicity is observed. As acidity is a characteristic of solid tumor, the two‐step strategy can serve as a universal and promising modality for safe and high‐performance nanoparticle‐based antitumor therapy.     

Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO₂‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.     

“All‐in‐One” Nanoparticles for Trimodality Imaging‐Guided Intracellular Photo‐magnetic Hyperthermia Therapy under Intravenous Administration

Great efforts have been devoted so far to combine nano‐magnetic hyperthermia and nano‐photothermal therapy to achieve encouraging additive therapeutic performance in vitro and in vivo with limitation to direct intratumoral injection and no guidance of multimodality molecular imaging. In this study, a novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) consisting of magnetic nanoparticles (MNPs), poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PES), Cyanine7 (Cy7), and 2‐deoxyglucose (2‐DG)‐polyethylene glycol is developed. They are then applied to combined photo‐magnetic hyperthermia therapy under intravenous administration that is simultaneously guided by trimodality molecular imaging. Remarkably, nanoparticles are found aggregated mainly in the cytoplasm of tumor cells in vitro and in vivo, and exhibit stealth‐like behavior with a long second‐phase blood circulation half‐life of 20.38 ± 4.18 h. Under the guidance of photoacoustic/near‐infrared fluorescence/magnetic resonance trimodality imaging, tumors can be completely eliminated under intracellular photo‐magnetic hyperthermia therapy with additive therapeutic effect due to precise hyperthermia. This study may promote a further exploration of such a platform for clinical applications.     

Multiple Layer‐by‐Layer Lipid‐Polymer Hybrid Nanoparticles for Improved FOLFIRINOX Chemotherapy in Pancreatic Tumor Models

The FOLFIRINOX regimen, a combination of three chemotherapy agents (5‐fluorouracil, irinotecan, oxaliplatin) and folinic acid (a vitamin B derivatives reducing the side effect of 5‐fluorouracil), has proved to be effective in the treatment of pancreatic cancer, and is more efficacious than the long‐term reference standard, gemcitabine. However, the FOLFIRINOX is associated with high‐grade toxicity, which markedly limits its clinical application. Encapsulation of drugs in nanocarriers that selectively target cancer cells promises to be an effective method for co‐delivery of drug combinations and to mitigate the side effects of conventional chemotherapy. Here we reported the development of multiple layer‐by‐layer lipid‐polymer hybrid nanoparticles with targeting capability that show excellent biocompatibility and synergistically combine the favorable properties of liposomes and polymer nanoparticles. Relative to nanoparticles consisting of polymer alone, these novel nanocarriers have a long half‐life in vivo and a higher stability in serum. The nanocarriers were loaded with the three active antitumor constituents of FOLFIRINOX regimen. Little drugs were released from the nanoparticles in phosphate buffered saline (PBS) solution, but the cargoes were quickly released after the nanoparticles were taken up by tumor cells. These innovative drug‐loaded nanoparticles achieved higher antitumor efficacy and showed minimal side effects compared with the FOLFIRINOX regimen alone. Our study suggested that the multiple layer‐by‐layer hybrid nanoparticles have great potential for improving the chemotherapeutic efficacy for the patients with pancreatic cancer. This platform also provides new opportunities for tailored design of nanoparticles that may offer therapeutics benefits for a range of other tumors.     

Imaging‐Guided pH‐Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near‐Infrared Light

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue‐penetrating near‐infrared light (NIR) light. Herein, we synthesize manganese (Mn²⁺)‐doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (¹O₂) to kill cancer cells. A layer‐by‐layer (LbL) self‐assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and ¹O₂ generation. By further coating UCNP@2xCe6 with an outer layer of charge‐reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6‐DMMA‐PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR‐induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn²⁺‐doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6‐DMMA‐PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge‐reversible UCNP@2xCe6‐DMMA‐PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor‐homing of these pH‐responsive charge‐switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH‐responsive PDT agents promising in cancer theranostics.     

Precise RNA Editing: Cascade Self-Uncloaking Dual-Prodrug Nanoassemblies Based on CRISPR/Cas13a for Pleiotropic Immunotherapy of PD-L1-Resistant Colorectal Cancer

CRISPR/Cas13a is a powerful genome editing system for RNA knockdown that holds enormous potential for cancer treatment by targeting currently undruggable oncogenes or immune checkpoints. However, the precise intratumoral activation of CRISPR/Cas13a to maximize the therapeutic efficiency while guaranteeing biosafety remains a daunting challenge. Here, a cascade self-uncloaking nanoassembly (SRC) based on a dual-prodrug comprising SN38 and Cas13a/RNP is developed, and the external encapsulation is performed by coating with a ROS-responsive probe, which is stimulated by the tumor microenvironment to achieve the efficient NIR-II imaging by CH10055 due to disaggregation into single molecules, while the second release of prodrug in the hypoxic environment enables targeted controlled release. SN38 not only induces immunogenic cell death (ICD), but significantly combats the immunosuppressive microenvironment of colorectal cancer in combination with the RNA editing targeting the novel immune checkpoint TIM3 to regulate the cGAS-STING pathways, resulting in synergistic activation of both innate and adaptive immunity. The treatment of SRC exhibits a tenfold increase in tumor regression of α-PD-L1 in PD-L1-resistant orthotopic and xenograft models by inducing effective tumor immune infiltration. These results demonstrate the feasibility of using CRISPR/Cas13a in cancer treatment, and SRC holds immense promise as a neoadjuvant strategy for enhancing CRC immunotherapy.     

Protease-Activatable Nanozyme with Photoacoustic and Tumor-Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy

Despite the promise of ferrotherapy in cancer treatment, current ferrous therapeutics suffer from compromised antitumor ferroptosis efficacy and low specificity for tumors. Herein, a protease-activatable nanozyme (Fe₃O₄@Cu_1.77Se) is reported for photoacoustic and tumor-enhanced magnetic resonance imaging (MRI)-guided second near-IR photothermal ferroptosis cancer therapy. Fe₃O₄@Cu_1.77Se remains stable in physiological conditions, but disintegrates to increase reactive intratumoral ferrous supply for elevated hydroxyl radical generation by Fenton reaction and GSH depletion in response to overexpressed matrix metalloproteinases in tumor microenvironment, leading to amplified ferroptosis of tumor cells as well as enhanced T₂-weighted MRI contrast. Further integration with second near-IR photoirradiation to generate localized heat not only triggers effective photothermal therapy and photoacoustic imaging but more importantly, potentiates Fenton reaction to promote ferroptotic tumor cell death. Such synergism leads to the polarization of tumor-associated macrophage from the tumor-promoting M2 type to the tumor-killing M1 type, and induces the immunogenic cells death of tumor cells, which in turn promotes the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumor, contributing to significant tumor suppression. This study presents a novel activatable ferrous nanotheranostics for spatial-temporal control over antitumor ferroptosis responses.     

Poly(Ferulic Acid) with an Anticancer Effect as a Drug Nanocarrier for Enhanced Colon Cancer Therapy

As colorectal cancer is the fourth leading cause of cancer‐related death worldwide, colorectal cancer therapy requires new strategies for improved therapeutic effects. Recently, nanodrug carriers have emerged to weaken the systemic toxicity of chemotherapy drugs and strengthen the treatment effectiveness against colorectal cancer. In this report, ferulic acid, a plant derivative, is polycondensed into poly(ferulic acid) (PFA) for the first time to serve as an excellent drug carrier with anticancer performance. PFA self‐assembles into nanoparticles by nanoprecipitation, and the screened PFA nanoparticles (NPs) have a diameter of ≈100 nm and possess a reasonable drug‐loading capacity of ≈8.3% of paclitaxel (PTX). Evaluation of CT26 cells and a corresponding mouse model indicates remarkable inhibition of colon cancer with PTX‐loaded PFA nanoparticles (PFA@PTX NPs) treatment both in vitro and in vivo. Meanwhile, evaluation of blank PFA NPs in a tumor mouse model also shows tumor inhibition, confirming that PFA itself has an anticancer effect in vivo. Overall, the novel nanoparticles based on poly(ferulic acid) can not only effectively deliver chemodrugs but also provide additional anticancer therapeutic effects, providing a promising platform for clinical colon cancer therapy.     

Injectable Adhesive Hydrogel as Photothermal-Derived Antigen Reservoir for Enhanced Anti-Tumor Immunity

Low vaccine immunogenicity and tumor heterogenicity greatly limit the therapeutic effect of tumor vaccine. In this study, a novel injectable adhesive hydrogel, based on thermosensitive nanogels containing catechol groups and loaded with in situ-forming MnO₂ nanoparticles, is constructed to overcome these issues. The concentrated nanogel dispersion transforms into an adhesive hydrogel in situ after intratumoral injection. The photothermal effect of the loaded MnO₂ nanoparticles induces immunogenic cell death to release mass autologous tumor-derived protein antigens under near-infrared irradiation, which act as ideal immune stimulating substances avoiding the problem of tumor heterogenicity and are captured by the in situ-forming adhesive hydrogel. The antigens-captured adhesive hydrogel acts as an “antigen reservoir” and releases these captured antigens to recruit more dendritic cells to stimulate an intensive and lasting anti-tumor immune response mediated by CD8⁺ T cells. The primary tumors can be almost completely disappeared within 4 days without relapse, and the growth of the distal tumors and rechallenged tumors are also effectively inhibited by the treatment with the injectable adhesive hydrogel-based photothermal therapy. Therefore, the proposed “antigen reservoir” strategy shows the great potential application as an in situ-forming personalized vaccine to enhancing the cancer immune therapy.