Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

High level of C (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

Flexocatalysis Enhances Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) is long-standing suffered from elevated tumor interstitial fluid pressure (TIFP) and prevalent hypoxic microenvironment within the solid malignancies. Herein, sound-activated flexocatalysis is developed to overcome the dilemma of PDT through both enhancing tumor penetration of photosensitizers by reducing TIFP and establishing an oxygen-rich microenvironment. In detail, a Schottky junction is constructed by flexocatalyst MoSe2 nanoflowers and Pt. Subsequently, the Schottky junction is loaded with the photosensitizer indocyanine green (ICG) and encapsulated within tumor cytomembrane to constitute a bionic-flexocatalytic nanomedicine (MPI@M). After targeting the tumor, MPI@M orchestrates flexocatalytic water splitting in tumor interstitial fluid under acoustic stimulation to lower TIFP, which boosted the tumor penetration of ICG. Concurrently, the oxygen released from the flexocatalytic water splitting overcomes the limitation of hypoxia against PDT. Furthermore, superfluous singlet oxygen generated by PDT can induce mitochondrial dysfunction for further tumor cell apoptosis. After 60 min of flexocatalysis, both the 30% decrease of TIFP and the relieved tumor hypoxia are observed, significantly promoting the therapeutic effect of PDT. Consequently, MoSe2/Pt junction nanoflowers, with the excellent flexocatalytic performance, hold significant potential for future applications in biocatalytic cancer therapies.

Natural MOF-Like Photocatalytic Nanozymes Alleviate Tumor Pressure for Enhanced Nanodrug Penetration.

In oncological nanomedicine, overcoming the dual-phase high interstitial pressure in the tumor microenvironment is pivotal for enhancing the penetration and efficacy of nanotherapeutics. The elevated tumor interstitial solid pressure (TISP) is largely attributed to the overaccumulation of collagen in the extracellular matrix, while the increased tumor interstitial fluid pressure (TIFP) stems from the accumulation of fluid due to the aberrant vascular architecture. In this context, metal-organic frameworks (MOFs) with catalytic efficiency have shown potential in degrading tumor interstitial components, thereby reducing interstitial pressure. However, the potential biotoxicity of the organic components of MOFs limits their clinical translation. To circumvent this, a MOF-like photocatalytic nanozyme, RPC@M, using naturally derived cobalt phytate (CoPA) and resveratrol (Res) is developed. This nanozyme not only facilitates the decomposition of water in the tumor interstitium under photoactivation to reduce TIFP, but also generates an abundance of reactive oxygen species through its peroxidase-like activity to exert cytotoxic effects on tumor cells. Moreover, Res contributes to the reduction of collagen deposition, thereby lowering TISP. The concurrent diminution of both TISP and TIFP by RPC@M leads to enhanced tumor penetration and potent antitumor activity, presenting an innovative approach in constructing tumor therapeutic nanozymes from natural products.

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

Flexocatalytic Reduction of Tumor Interstitial Fluid/Solid Pressure for Efficient Nanodrug Penetration.

The practical efficacy of nanomedicines for treating solid tumors is frequently low, predominantly due to the elevated interstitial pressure within such tumors that obstructs the penetration of nanomedicines. This increased interstitial pressure originates from both liquid and solid stresses related to an undeveloped vascular network and excessive fibroblast proliferation. To specifically resolve the penetration issues of nanomedicines for tumor treatment, this study introduces a holistic "dual-faceted" approach. A treatment platform predicated on the WS2/Pt Schottky heterojunction was adopted, and flexocatalysis technology was used to disintegrate tumor interstitial fluids, thus producing oxygen and reactive oxygen species and effectively mitigating the interstitial fluid pressure. The chemotherapeutic agent curcumin was incorporated to further suppress the activity of cancer-associated fibroblasts, minimize collagen deposition in the extracellular matrix, and alleviate solid stress. Nanomedicines achieve homologous targeting by enveloping the tumor cell membrane. It was found that this multidimensional strategy not only alleviated the high-pressure milieu of the tumor interstitium─which enhanced the efficiency of nanomedicine delivery─but also triggered tumor cell apoptosis via the generated reactive oxygen species and modulated the tumor microenvironment. This, in turn, amplified immune responses, substantially optimizing the therapeutic impacts of nanomedicines.

Piezoelectric Catalysis Induces Tumor Cell Senescence to Boost Chemo-Immunotherapy.

Cellular senescence, a vulnerable state of growth arrest, has been regarded as a potential strategy to weaken the resistance of tumor cells, leading to dramatic improvements in treatment efficacy. However, a selective and efficient strategy for inducing local tumor cellular senescence has not yet been reported. Herein, piezoelectric catalysis is utilized to reduce intracellular NAD+ to NADH for local tumor cell senescence for the first time. In detail, a biocompatible nanomedicine (BTO/Rh-D@M) is constructed by wrapping the piezoelectric BaTiO3/(Cp*RhCl2)2 (BTO/Rh) and doxorubicin (DOX) in the homologous cytomembrane with tumor target. After tumors are stimulated by ultrasound, negative and positive charges are generated on the BTO/Rh by piezoelectric catalysis, which reduce the intracellular NAD+ to NADH for cellular senescence and oxidize H2O to reactive oxygen species (ROS) for mitochondrial damage. Thus, the therapeutic efficacy of tumor immunogenic cell death-induced chemo-immunotherapy is boosted by combining cellular senescence, DOX, and ROS. The results indicate that 23.9% of the piezoelectric catalysis-treated tumor cells senesced, and solid tumors in mice disappeared completely after therapy. Collectively, this study highlights a novel strategy to realize cellular senescence utilizing piezoelectric catalysis and the significance of inducing tumor cellular senescence to improve therapeutic efficacy.

Cascaded Antitumor Therapy Excited by Dual Nanozymes Based on Energy Restriction and Photocatalysis.

In nanocatalytic medicine, drugs can be transformed into toxic components through highly selective and highly specific catalytic reactions in the tumor microenvironment, avoiding toxic side effects on normal tissues. Due to the coexistence of Ce3+ and Ce4+, CeO2 is endowed with dual nanozyme activities. Herein, CeO2 nanoparticles served as templates to construct a biomimetic nanodrug delivery system (C/CeO2@M) by electrostatic adsorption of carbon quantum dots (CQDs) and coating a homologous tumor cytomembrane. After homologous targeting to tumors, the CQDs emitted 350-600 nm light under 660 nm laser irradiation by upconversion luminescence, which caused a CeO2-mediated photocatalytic reaction to generate reactive oxygen species. The catalase-like activity of CeO2-enabled converting excess H2O2 to O2, which not only alleviated tumor hypoxia and promoted intratumor drug delivery but also provided substrates for subsequent catalytic reactions. Meanwhile, the phosphatase activity of CeO2 could consume adenosine triphosphate (ATP) to block the energy supply for tumor cells, thus limiting cell proliferation and metastasis. The strategy of energy restriction and photocatalysis of dual nanozyme stimulation offers great potentials in enhancing drug penetration and eradicating solid tumors.

Revisiting the glass transition and dynamics of supercooled benzene by calorimetric studies.

The glass transition and dynamics of benzene are studied in binary mixtures of benzene with five glass forming liquids, which can be divided into three groups: (a) o-terphenyl and m-xylene, (b) N-butyl methacrylate, and (c) N,N-dimethylpropionamide and N,N-diethylformamide to represent the weak, moderate, and strong interactions with benzene. The enthalpies of mixing, ΔH(mix), for the benzene mixtures are measured to show positive or negative signs, with which the validity of the extrapolations of the glass transition temperature T(g) to the benzene-rich regions is examined. The extrapolations for the T(g) data in the mixtures are found to converge around the point of 142 K, producing T(g) of pure benzene. The fragility m of benzene is also evaluated by extrapolating the results of the mixtures, and a fragility m ∼ 80 is yielded. The obtained T(g) and m values for benzene allow for the construction of the activation plot in the deeply supercooled region. The poor glass formability of benzene is found to result from the high melting point, which in turn leads to low viscosity in the supercooled liquid.