Photo-metallo-immunotherapy: Fabricating Chromium-Based Nanocomposites to Enhance CAR-T Cell Infiltration and Cytotoxicity against Solid Tumors.

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can "warm" the "cold" tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.

Black phosphorus-based nanoparticles induce liver cancer cell mitochondrial apoptosis and immune cell tumor infiltration for enhancing dendritic cell therapy.

Cellular immunotherapy is a crucial aspect of current tumor immunotherapy, though it presents several challenges such as immune cell dysfunction, limited recognition of neoantigens, and inadequate lymphocyte infiltration into the tumor microenvironment. This study proposes a novel approach utilizing a combination of dendritic cell (DC)-based cellular immunotherapy and a photothermal nanoadjuvant black phosphorus (BP) nanoparticles to overcome these challenges. A new platform called PLGA@BP-R848, which consists of modifying poly-(lactic-co-glycolic acid) (PLGA) onto BP nanosheets loading the immune adjuvant R848. The PLGA@BP-R848 nanoparticles demonstrated exceptional drug delivery and release capabilities, as well as a photothermal effect, biocompatibility, and the ability to activate the mitochondrial apoptotic pathway Blc-2-Bax-Cytochrome c-caspase-3 and inhibit the PI3K-AKT-mTOR signaling pathway. In a hepatocellular carcinoma mouse model, the binding of PLGA@BP-R848 nanoparticles and dendritic cells primed with GPC3 peptides, successfully induced a systemic anti-tumor immune response. PLGA@BP-R848 nanoparticles bolster immune cell infiltration into tumors and induce cancer cell apoptosis. The synergistic therapy involving dendritic cells and photothermal nanoadjuvant effectively suppressed tumor growth, and facilitated the formation of tertiary lymphatic structures (TLS) in tumors. This study presents a novel approach in using photothermal nanoadjuvants to advance antitumor effect of cellular immunotherapy, such as DCs therapy.

Phosphoglycerate Kinase 1: An Effective Therapeutic Target in Cancer.

Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5'-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1's expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.

Prodrug-Loaded Zirconium Carbide Nanosheets as a Novel Biophotonic Nanoplatform for Effective Treatment of Cancer.

Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia-induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT-photosensitizer and on-demand designed anticancer prodrug SN38-Nif, which is released and activated by photothermia and tumor-overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia-induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.

Biocompatible Two-Dimensional Titanium Nanosheets for Multimodal Imaging-Guided Cancer Theranostics.

Photothermal therapy (PTT) based on two-dimensional (2D) nanomaterials has shown significant potential in cancer treatment. However, developing 2D nanomaterial-based theranostic agents with good biocompatibility and high therapeutic efficiency remains a key challenge. Bulk titanium (Ti) has been widely used as biomedical materials for their reputable biocompatibility, whereas nanosized Ti with a biological function remains unexplored. In this work, the 2D Ti nanosheets (NSs) are successfully exfoliated from nonlayer bulk Ti and utilized as an efficient theranostic nanoplatform for dual-modal computed tomography/photoacoustic (CT/PA) imaging-navigated PTT. Besides the excellent biocompatibility obtained by TiNSs as expected, they are found to show strong absorption ability with an extinction coefficient of 20.8 L g-1 cm-1 and high photothermal conversion ability with an efficiency of 61.5% owing to localized surface plasmon resonances, which exceeds most of other well-known photothermal agents, making it quite promising for PTT against cancer. Furthermore, the metallic property and light-heat-acoustic transformation endow 2D Ti with the strong CT/PA imaging signal and efficient cancer therapy, simultaneously. This work highlights the enormous potential of nanosized Ti in both the diagnosis and treatment of cancer. As a paradigm, this study also paves a new avenue for the elemental transition-metal-based cancer theranostics.

Two-Dimensional MXene (Ti3C2)-Integrated Cellulose Hydrogels: Toward Smart Three-Dimensional Network Nanoplatforms Exhibiting Light-Induced Swelling and Bimodal Photothermal/Chemotherapy Anticancer Activity.

Two-dimensional (2D) MXenes have recently been shown to be promising for applications in anticancer photothermal therapy (PTT), owing to their outstanding photothermal performance. However, as with the other inorganic 2D nanomaterials, the MXene-based nanoplatforms lack the appropriate biocompatibility and stability in physiological conditions, targeting capability, and controlled release of drug, for cancer therapy. Fabricating a smart MXene-based nanoplatform for the treatment of cancer therefore remains a challenge. In this work, composite hydrogels based on cellulose and Ti3C2 MXene, were synthesized for the first time. We have shown that the cellulose/MXene composite hydrogels possess rapid response near-infrared-stimulated characteristics, which present as a continuous dynamic process in water. As a result, when loaded with the anticancer drug doxorubicin hydrochloride (DOX), the cellulose/MXene hydrogels are capable of significantly accelerating the DOX release. This behavior is attributed to the expansion of the pores within the three-dimensional cellulose-based networks, triggered by illumination with an 808 nm light. Capitalizing on their excellent photothermal performance and controlled, sustained release of DOX, the cellulose/MXene hydrogels are utilized as a multifunctional nanoplatform for tumor treatment by intratumoral injection. The results showed that the combination of PTT and prolonged adjuvant chemotherapy delivered using this nanoplatform was highly efficient for instant tumor destruction and for suppressing tumor relapse, demonstrating the potential of the nanoplatform for application in cancer therapy. Our work not only opens the door for the fabrication of smart MXene-based nanocomposites, along with their promising application against cancer, but also paves the way for the development of other inorganic 2D composites for applications in biomedicine.

Conceptually Novel Black Phosphorus/Cellulose Hydrogels as Promising Photothermal Agents for Effective Cancer Therapy.

Black phosphorus (BP) has recently emerged as an intriguing photothermal agent in photothermal therapy (PTT) against cancer by virtue of its high photothermal efficiency, biocompatibility, and biodegradability. However, naked BP is intrinsically characterized by easy oxidation (or natural degradation) and sedimentation inside the tumor microenvironment, leading to a short-term therapeutic and inhomogeneous photothermal effect. Development of BP-based nanocomposites for PTT against cancer therefore remains challenging. The present work demonstrates that green and injectable composite hydrogels based on cellulose and BP nanosheets (BPNSs) are of great efficiency for PTT against cancer. The resultant cellulose/BPNS-based hydrogel possesses 3D networks with irregular micrometer-sized pores and thin, strong cellulose-formed walls and exhibits an excellent photothermal response, enhanced stability, and good flexibility. Importantly, this hydrogel nanoplatform is totally harmless and biocompatible both in vivo and in vitro. This work may facilitate the development of BP-polymer-based photothermal agents in the form of hydrogels for biomedical-related clinic applications.