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Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy. Some chemotherapeutic drugs, such as doxorubicin, induce immunogenic cell death (ICD) and promote anti-tumor immune responses. Here the authors report that the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) reduces the expression of PD-L1 in cancer cells and enhances doxorubicin-induced ICD, promoting T cell infiltration and reducing tumor growth in preclinical models.

Nanoparticles have been developed for tumor treatment due to the enhanced permeability and retention effects. However, lack of specific cancer cells selectivity results in low delivery efficiency and undesired side effects. In that case, the stimuli-responsive nanoparticles system designed for the specific structure and physicochemical properties of tumors have attracted more and more attention of researchers. Esterase-responsive nanoparticle system is widely used due to the overexpressed esterase in tumor cells. For a rational designed esterase-responsive nanoparticle, ester bonds and nanoparticle structures are the key characters. In this review, we overviewed the design of esterase-responsive nanoparticles, including ester bonds design and nano-structure design, and analyzed the fitness of each design for different application. In the end, the outlook of esterase-responsive nanoparticle is looking forward.

The emergence of nanomaterials for drug delivery provides the opportunity to avoid the side effects of systemic drug administration and injury caused by the removal of tumors, delivering great promise for future cancer treatments. However, the efficacy of current nano drugs is not significantly better than that of the original drug treatments. The important reason is that nano drugs enter the tumor vasculature, remaining close to the blood vessels and unable to enter the tumor tissue or tumor cells to complete the drug delivery process. The low efficiency of drug penetration into tumors has become a bottleneck restricting the development of nano-drugs. Herein, we present a systematic overview of recent advances on the design of nano-drug carriers in drug delivery systems for enhancing drug penetration into tumors. The review is organized into four sections: The drug penetration process in tumor tissue includes paracellular and transcellular transport, which is summarized first. Strategies that promote tumor penetration are then introduced, including methods of remodeling the tumor microenvironment, charge inversion, dimensional change, and surface modification of ligands which promote tissue penetration. Conclusion and the prospects for the future development of drug penetration are finally briefly illustrated. The review is intended to provide thoughts for effective treatment of cancer by summarizing strategies for promoting the endocytosis of nano drugs into tumor cells.

Adsorption is a common method to treat organic dye pollution in industrial wastewater. Selective adsorption and reuse can greatly reduce the waste of adsorbents. Among the adsorbents of many different materials, the porous polymer microspheres as adsorbents have the characteristics of good adsorption effect, wide application range and large modification space, showing the unique advantages different from the traditional carbon materials. As a new kind of porous polymer material, polyionic liquid porous microspheres have great potential in the field of organic dye adsorption. In this paper, the selective adsorption of anionic organic dyes by a novel monodisperse pyridine polyionic liquid microsphere as an organic dye adsorbent was studied and the adsorption mechanism was studied.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-( N -oxide- N , N -diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion–drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion–drug conjugates should facilitate the design of translational anticancer nanomedicines. Conjugates of small-molecule anticancer drugs with a polyzwitterion that has negligible interaction with proteins and a weak interaction with phospholipids eradicate large tumours and patient-derived tumour xenografts in mice.

The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on‐demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines’ composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine‐oxide)‐block‐poly(ε‐caprolactone) (PTAO‐PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation. Polyzwitterionic micelles of poly(tertiary amine‐oxide)‐block‐poly(ε‐caprolactone) amphiphiles have been developed as a generic platform for efficient cancer drug delivery. The micelles' unique affinity toward cell membrane enables long blood circulation through red blood cell‐hitchhiking, transcytosis‐mediated enhanced tumor accumulation and penetration, fast cellular internalization, and finally mitochondrial targeting to overcome tumor multidrug resistance.

Significant challenges persist in enhancing the delivery efficiency of tumor nanomedicines, predominantly due to the difficulty of successfully surpassing pathophysiological barriers. Enhancing tumor penetration of nanomedicines in such conditions represents a pivotal goal in advancing anticancer nanotherapeutics. Transcytosis emerges as a promising solution in this context, addressing the limitations of passive drug delivery. By harnessing diverse stimuli to induce transcytosis, nanocarriers can achieve precise drug delivery and deep tumor penetration, resulting in high therapeutic efficacy and reduced systemic exposure to the therapeutic compound. This review briefly examines various stimuli‐responsive nanosystems and offers an overview and outlook on the development of stimuli‐responsive nanocarriers for transcytosis‐based cancer drug delivery, aiming to provide informative insights for the design of nanomedicines capable of deep tissue penetration and enhanced therapeutic efficacy. Stimuli‐responsive transcytosis strategy utilizes various triggers to induce cell transcytosis of nanomedicine for precise and deep tumor penetration, thereby overcoming passive delivery limitations and enhancing tumor drug efficacy. This review provides an overview and outlook of transcytosis research and diverse stimuli‐responsive transcytosis nanosystems, offering insights for designing effective nanomedicines with improved tumor penetration.

Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles. Existing methods use bifunctional chimaeras for extracellular protein degradation but rely on specific lysosome-targeting receptors, raising resistance issues. Here, the authors develop MONOTAB, a monofunctional platform that degrades extracellular proteins and vesicles without receptor dependency.

Biofluorescence imaging enables real-time, visual detection of biomolecules, cells and tissues/organs on a three-dimensional scale. And it can track the various physiological processes of the organism and understand the relationship between biomolecules and their structure and function. Near-infrared imaging has a high temporal and spatial resolution, low damage to biological tissues and strong penetrating capability, good sensitivity and low background fluorescence interference, which are the advantages of imaging technology. However, at present, the deficiencies of fluorescent groups include relatively low fluorescence quantum yield and unfavorably short emission wavelength in the NIR region, especially in the second near-infrared window (1000–1700 nm, NIR-II). In the in vivo processes and applications of NIR fluorescence materials, biocompatibility, fluorescence quantum efficiency and adjustability of excitation and emission wavelengths in the NIR region should be considered. Therefore, organic polymeric materials are ideal for the construction of the NIR fluorescence probe. In this review, the synthesis and applications of NIR fluorescence polymers were summarized and the future trend has prospected as well.