Hypoxia-accelerating pyroptosis nanoinducers for promoting image-guided cancer immunotherapy.

Precise image-guided cancer immunotherapy holds immense potential in revolutionizing cancer treatment. The strategies facilitating activatable imaging and controlled therapeutics are highly desired yet to be developed. Herein, we report a new pyroptosis nanoinducer that integrates aggregation-induced emission luminogen (AIEgen) and DNA methyltransferase inhibitor with hypoxia-responsive covalent organic frameworks (COFs) for advanced image-guided cancer immunotherapy. We first synthesize and compare three donor-acceptor type AIEgens featuring varying numbers of electron-withdrawing units, and find that the incorporation of two acceptors yields the longest response wavelength and most effective photodynamic therapy (PDT) property, surpassing the performance of analogs with one or three acceptor groups. A COF-based nanoplatform containing AIEgen and pyroptosis drug is successfully constructed via the one-pot method. The intra-COF energy transfer significantly quenches AIEgen, in which both fluorescence and PDT properties greatly enhance upon hypoxia-triggered COF degradation. Moreover, the photodynamic process exacerbates hypoxia, accelerating pyroptosis drug release. The nanoagent enables sensitive delineation of tumor site through in situ activatable fluorescence signature. Thanks to the exceptional ROS production capabilities and hypoxia-accelerating drug release, the nanoagent not only inhibits primary tumor growth but also impedes the progression of distant tumors in 4T1 tumor-bearing mice through potent pyroptosis-mediated immune response. This research introduces a novel strategy for achieving activatable phototheranostics and self-accelerating drug release for synergetic cancer immunotherapy.

Hypoxia-responsive AIEgens for precise disease theranostics.

Specific biomarker-activatable probes have revolutionized theranostics, being beneficial for precision medicine. Hypoxia is a critical pathological characteristic prevalent in numerous major diseases such as cancers, cardiovascular disorders, inflammatory diseases, and acute ischemia. Aggregation-induced emission luminogens (AIEgens) have emerged as a promising tool to tackle the biomedical issues. Of particular significance are the hypoxia-responsive AIEgens, representing a kind of crucial probe capable of delicately sensing and responding to the hypoxic microenvironment, thereby enhancing the precision of disease diagnosis and treatment. In this review, we summarize the recent advances of hypoxia-responsive AIEgens for varied biomedical applications. The hypoxia-responsive structures based on AIEgens, such as azobenzene, nitrobenzene, and N-oxide are presented, which are in response to the reduction property to bring about significant alternations in response spectra and/or fluorescence intensity. The bioapplications including imaging and therapy of tumor and ischemia diseases are discussed. Moreover, the review sheds light on the future challenges and prospects in this field. This review aims to provide comprehensive guidance and understanding into the development of activatable bioprobes, especially the hypoxia-responsive AIEgens for improving the diagnosis and therapy outcome of related diseases.

Semiconducting Polymers for Cancer Immunotherapy.

As a monumental breakthrough in cancer treatment, immunotherapy has attracted tremendous attention in recent years. However, one challenge faced by immunotherapy is the low response rate and the immune-related adverse events (irAEs). Therefore, it is important to explore new therapeutic strategies and platforms for boosting therapeutic benefits and decreasing the side effects of immunotherapy. In recent years, semiconducting polymer (SP), a category of organic materials with π-conjugated aromatic backbone, has been attracting considerable attention because of their outstanding characteristics such as excellent photophysical features, good biosafety, adjustable chemical flexibility, easy fabrication, and high stability. With these distinct advantages, SP is extensively explored for bioimaging and photo- or ultrasound-activated tumor therapy. Here, the recent advancements in SP-based nanomedicines are summarized for enhanced tumor immunotherapy. According to the photophysical properties of SPs, the cancer immunotherapies enabled by SPs with the photothermal, photodynamic, or sonodynamic functions are highlighted in detail, with a particular focus on the construction of combination immunotherapy and activatable nanoplatforms to maximize the benefits of cancer immunotherapy. Herein, new guidance and comprehensive insights are provided for the design of SPs with desired photophysical properties to realize maximized effectiveness of required biomedical applications.

Dual-stimulus phototherapeutic nanogel for triggering pyroptosis to promote cancer immunotherapy.

Pyroptosis is a highly inflammatory programmed cell death that activates inflammatory response, reverses immunosuppression and promotes systemic immune response for solid tumors treatment. However, the uncontrollable and imprecise process of pyroptosis stimulation leads to a scanty therapeutic effect. Here, we report a GSH/ROS dual response nanogel system (IMs) that can actively target the overexpressed mannose receptor (MR) of cancer cells, serve ultra-stable photothermal capacity of indocyanine green (ICG), induce cell pyroptosis and achieve enhanced tumor immune response. Photo-triggered IMs induce cytoplasmic Ca2+ introgression and activate caspase-3 through photo-activated ICG. The disconnect of SeSe bonds can break the oxidation and reduction balance of tumor cells, causing oxidative stress and synergistically enhancing caspase-3 cleavage, and regulating cell pyroptosis ultimately. Combined with anti-programmed death receptor 1 (anti-PD-1), the nanogel system not only effectivly suppress both primary tumor and distance tumor but also prolong the survival period of mice. This work introduces a strategy to optimize the photothermal performance of ICG and enhances tumor immune response mediated by triggering pyroptosis, which provides an impressive option for immune checkpoint blockade therapy.

Bioengineering of BRAF and COX2 inhibitor nanogels to boost the immunotherapy of melanoma via pyroptosis.

Glutathione-responsive nanogels (CDNPs) crosslinked via crosslinker DBHD with the BRAF inhibitor dabrafenib and the COX2 inhibitor celecoxib were fabricated. The CDNPs can effectively induce tumor cell pyroptosis to activate robust antitumor immunity. Additionally, CDNPs combined with αPD-1 antibody greatly inhibited tumor growth in a melanoma mouse model with a prolonged survival time.

Reduction-triggered polycyclodextrin supramolecular nanocage induces immunogenic cell death for improved chemotherapy.

Polycyclodextrin-based supramolecular nanoplatform crosslinked by stimuli-responsive moiety shows great promise in cancer therapy owing to its superior bio-stability and feasible modification of architectures. Here, the endogenous glutathione (GSH)-responsive polycyclodextrin supramolecular nanocages (PDOP NCs) are constructed by covalent crosslinking of multiple ß-cyclodextrin (ß-CD) molecules. The polycyclodextrin provide sites for conjugation of chemotherapeutic doxorubicin (DOX). Meanwhile, the PDOP NCs are stabilized by multiple interactions including host-guest interaction between DOX and ß-CD and hydrogen bonds between ß-CD units. The supramolecular crosslinked structure endowed the nanocage with high stability and drug loading capacity. Tons of GSH-sensitive disulfide linkages in PDOP NCs were broken at tumor cells, promoting tumor-specific DOX release. Besides, the redox equilibrium in tumor microenvironment could be disturbed due to GSH depletion, which further sensitized the DOX effects and alleviated drug resistance, facilitating inducing immunogenic cell death effect for enhanced chemotherapy, thereby achieving efficient tumor suppression and prolonged survival. Thus, the versatile polycyclodextrin-based supramolecular nanocage provides a novel and efficient drug delivery strategy for cancer treatment.

Immunomodulatory-Photodynamic Nanostimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy.

Cancer immunotherapy is restricted to immune resistance caused by immunosuppressive tumor microenvironment. Pyroptosis involved in antitumor immunotherapy as a new schedule is prospective to reverse immunosuppression. Herein, acidic tumor microenvironment (TME)-evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis-mediated immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells' (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement an aforementioned two-pronged strategy to enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy.

Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.

Stepwise Size Shrinkage Cascade-Activated Supramolecular Prodrug Boosts Antitumor Immunity by Eliciting Pyroptosis.

Effective pyroptosis induction is a promising approach to potentiate cancer immunotherapy. However, the actual efficacy of the present pyroptosis inducers can be weakened by successive biological barriers. Here, a cascaded pH-activated supramolecular nanoprodrug (PDNP) with a stepwise size shrinkage property is developed as a pyroptosis inducer to boost antitumor immune response. PDNPs comprise multiple poly(ethylene glycol) (PEG) and doxorubicin (DOX) drug-polymer hybrid repeating blocks conjugated by ultra-pH-sensitive benzoic imine (bzi) and hydrazone (hyd) bonds. The PEG units endow its "stealth" property and ensure sufficient tumor accumulation. A sharp switch in particle size and detachment of PEG shielding can be triggered by the acidic extracellular pH to achieve deep intratumor penetration. Following endocytosis, second-stage size switching can be initiated by more acidic endolysosomes, and PDNPs disassociate into ultrasmall cargo to ensure accurate intracellular delivery. The cascaded pH activation of PDNPs can effectively elicit gasdermin E (GSDME)-mediated pyroptosis to enhance the immunological response. In combination with anti-PD-1 antibody, PDNPs can amplify tumor suppression and extend the survival of mice, which suggests a powerful immune adjuvant and pave the way for high-efficiency immune checkpoint blockade therapy.

Active targeting redox-responsive mannosylated prodrug nanocolloids promote tumor recognition and cell internalization for enhanced colon cancer chemotherapy.

Despite the diversified therapeutic approaches for malignant tumors, chemotherapy remains the backbone of current cancer treatment. However, conventional chemotherapeutics was found to be associated with deficient recognition of tumor, low uptake efficiency, insolubility, short circulation, poor biocompatibility and low therapeutic outcomes. Herein, the active targeting redox-responsive mannosylated prodrug nanocolloids (HM NCs) were constructed for enhanced chemotherapy of colon cancer. HM NCs were prepared by the covalent cross-linking of 10-hydroxycamptothecin (HCPT) and mannose (MAN) via a redox-responsive cross-linker containing disulfide bonds, and modified with a moderate amount of polyethylene glycol (PEG). The large amount of mannose contained in HM NCs could actively target overexpressed mannose receptors on the surface of cancer cells and enhance cancer cell internalization through mannose receptor-mediated endocytosis. Owing to the combination of active targeting and the enhanced permeability and retention (EPR) passive targeting, HM NCs could effectively accumulate in tumors and high glutathione (GSH) in tumor microenvironment triggered cleavage of redox-responsive bonds and precise drug release. HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. The innovative HM NCs are expected to be conducive to overcoming the limitations of conventional chemotherapy for colon cancer and providing more choices for future clinical translation. STATEMENT OF SIGNIFICANCE: Despite the enhanced permeability and retention effect, the passive targeting can be interfered with by the complex biologic barriers in the body. In this study, an active targeting system (HM NCs) was constructed by covalent cross-linking of mannose and anticancer drug 10-hydroxycamptothecin via redox-responsive disulfide bonds for enhanced colon cancer chemotherapy. Mannosylation could promote hydrophilia and stability for prolonged blood circulation. Mannose could promote tumor recognition and cell internalization via mannose receptor-mediated endocytosis. High glutathione level could trigger the redox-responsive release of anticancer drugs and further induce cell apoptosis via DNA damage. The HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility.

Polyamino acid calcified nanohybrids induce immunogenic cell death for augmented chemotherapy and chemo-photodynamic synergistic therapy.

Background: Monotherapy for cancer treatment is limited by unstable efficacy and uncontrollable toxic side effects, while the multifunctional nanoplatform with complex preparation process cannot avoid the potential toxicity of each functional component. Methods: We exploited tumor-specific activated polyamino acid calcified nanoparticles (CHC NPs) as new-type oxidative stress amplification of anticancer drugs via building a safe and biodegradable multifunctional nanoplatform. Giving priority to chemotherapy, and synergizing chemodynamic therapy (CDT) with photodynamic therapy (PDT), this strategy was to achieve enhanced chemotherapy, simultaneously inducing immunogenic cell death and inhibiting tumor cell invasion. Results: Based on amorphous calcium carbonate, pH-responsive nanocarrier was prepared with classical chemotherapeutic drug 10-hydroxycamplothecin (HCPT) and photosensitizer Chlorin e6 (Ce6) to realize multifunctional nanotheranostics. Conclusion: Inventive calcified nanohybrids, where topoisomerase inhibited by HCPT to prevent DNA synthesis, the generation of •OH induced via Fenton reaction, along with a large amount of 1O2 produced by Ce6, might be a promising strategy for anti-tumor combination therapy in clinical translation.

Microenvironment-Responsive Prodrug-Induced Pyroptosis Boosts Cancer Immunotherapy.

The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.

Acid-Sensitive Supramolecular Nanoassemblies with Multivalent Interaction: Effective Tumor Retention and Deep Intratumor Infiltration.

It remains a conundrum to reconcile the contradiction between effective tumor retention and deep intratumor infiltration for nanotherapeutics due to the sophisticated drug delivery journey. Herein, we reported an acid-sensitive supramolecular nanoassemblies (DCD SNs) based on the multivalent host-gest inclusions of two polymer conjugates for conquering diverse physiological blockages and amplifying therapeutic efficacy. The multiple inclusions of repetitive units on the hydrophilic polymer backbone reinforced the binding affinity and induced robust self-assembly, ameliorating instability of the self-assemblies and facilitating to prolong the drug retention time. By virtue of the acid-sensitive Schiff base linkages, the supramolecular nanoassembly could respond to the unique tumor microenvironment (TME), dissociate, and transform into smaller particles (∼30 nm), thereby efficiently traversing the complicated extracellular matrix and irregular blood vessels to achieve deep intratumor infiltration. The acid-sensitive DCD SNs can absorb a large number of protons in the acidic lysosomal environment, causing the proton sponge effect, which was conducive to their escape from endolysosomes and accelerated lysosomal disruption, so that the active chemotherapeutic doxorubicin (DOX) could enter the nucleus well and exert severe DNA damage to induce apoptosis. This versatile supramolecular nanoplatform is anticipated to be a promising candidate to overcome the limitations of insufficient stability within the circulation and weak intratumor penetration.

Cylindrical polymer brushes-anisotropic unimolecular micelle drug delivery system for enhancing the effectiveness of chemotherapy.

Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements, and are considered as one of the most promising controlled delivery systems that can effectively improve the cancer therapeutic index. However, the majority of the polymer delivery systems are designed to be simple spherical nanostructures. To explore morphology/size-oriented delivery performance optimization, here, we synthesized three novel cylindrical polymer brushes (CPBs) by atom transfer radical polymerization (ATRP), which were cellulose-g-(CPT-b-OEGMA) (CCO) with different lengths (~86, ~40, and ~21 nm). The CPBs are composed of bio-degradable cellulose as the carrier, poly(ethylene glycol) methyl ether methacrylate (OEGMA) as hydrophily block, and glutathione (GSH)-responsive hydrophobic camptothecin (CPT) monomer as loaded anticancer drug. By controlling the chain length of the initiator, three kinds of polymeric prodrugs with different lengths (CCO-1, CCO-2, and CCO-3) could be self-organized into unimolecular micelles in water. We carried out comparative studies of three polymers, whose results verified that the shorter CPBs exhibited higher drug release efficiency, more cellular uptake, and enhanced tumor permeability, accompanied by shortened blood circulation time and lower tumor accumulation. As evidenced by in vivo experiments, the shorter CPBs exhibited higher anti-tumor efficiency, revealing that the size advantage has a higher priority than the anisotropic structure advantage. This provided vital information as to design an anisotropic polymer-based drug delivery system for cancer therapy.

Reduction-Responsive Chemo-Capsule-Based Prodrug Nanogel for Synergistic Treatment of Tumor Chemotherapy.

Chemotherapy is currently the most universal therapeutics to tumor treatment; however, limited curative effect and undesirable drug resistance effect are the two major clinical bottlenecks. Herein, we develop a two-in-one cross-linking strategy to prepare a stimuli-responsive prodrug nanogel by virtue of delivering a combination of chemotherapeutic drugs of 10-hydroxy camptothecin and doxorubicin for ameliorating the deficiencies of chemotherapy and amplifying the cancer therapeutic efficiency. The obtained prodrug nanogel has both high drug loading capacity and suitable nanoscale size, which are beneficial to the cell uptake and tumor penetration. Moreover, the chemotherapeutic drugs are released from the prodrug nanogel in response to the reductive tumor microenvironment, enhancing tumor growth inhibition in vitro and in vivo by the synergistic DNA damage. Based on these results, the unique prodrug nanogel would be a promising candidate for satisfactory tumor treatment-based chemotherapy by a simple but efficient strategy.

New hybridization coupling mechanism and enhanced sensitivity in a Cu2-xS@Au nanoparticle dimer.

To improve the refractive index sensitivity of a localized surface plasmon resonance (LSPR) sensor, we employ a new interparticle hybridization plasmon coupled resonance in a semiconductor-metal (Cu2-xS@Au) core-shell nanoparticle dimer (SMCSND), where the refractive index sensitivity can be improved by the generation of a tunable dual-band absorption spectrum at visible and near-infrared wavelengths. Owing to two LSPRs in different wavelength regions supported by the metal shell and semiconductor core, for the first time, we theoretically demonstrate that the new interparticle hybridization plasmon coupled mechanism in semiconductor-metal core-shell nanoparticle dimer depends not only on interparticle separation gap, but also on the nanoparticle shell thickness t. Electromagnetic model analysis reveals that there are two plasmon modes (Mode A and Mode C) associated with the interparticle hybridization plasmon coupled resonance, where the Mode C shows high sensitivity and figure of merit (FoM) to changes in the background dielectric medium. The tunability of the induced interparticle hybridization plasmon coupled resonance with different the separation distance and shell thickness can change the sensitivity and FoM of LSPR sensor in the visible to near-infrared region, which has broad application prospects.

New coupling mechanism of titanium nitride nanosphere dimers at short separation distances.

The coupled localized plasmon modes generated by a metal plasmonic nanoparticle (NP) dimer induces a stronger plasmon enhanced electromagnetic field as well as a stronger optical response compared to that of a single NP. Owing to the small Drude damping factor, however, the absorption bandwidth of noble metallic NPs is insufficiently broad. Herein, the near-field wide band coupling absorption for 25 nm diameter TiN nanospheres is investigated in a homo-dimer arrangement for various separation distances using the finite element method. An enhancement of the wide band coupling absorption and a red-shift is found, which can be explained by an uncomplicated dipole-dipole coupling model at interparticle distances greater than 5 nm. At short separation distances, the coupling absorption of the TiN dimer exhibits a tremendous change, which is diametrically opposite the results found for a Au dimer. This unexpected change phenomenon is shown by calculation and analysis to be owing to the change of the charge distribution approach at short separation distances, which is demonstrated to play a key role in the wide band coupling characteristic variation. With decreasing separation gap, a new coupling mechanism caused by surface charge properties is responsible for the decline in coupling absorption as well as the break in the ruler equations for both plasmon shift and temperature enhancement.