"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

Spatiotemporally controlled AuNPs@ZIF-8 based nanocarriers for synergistic photothermal/chemodynamic therapy.

High efficiency and spatio-temporal control remains a challenge for multi-modal synergistic cancer therapy. Herein, based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), a spatio-temporal controllable photothermal/ chemical dynamic/ chemotherapy three modal synergistic anti-tumor nano-carrier (HAZD) was developed. HAZD has a size of 128.75 ± 11.86 nm, a drug loading ratio of 21.5 ± 2.2 % and an encapsulation efficiency of 71.8 ± 1.7 %. Stability, acid responsive release character, outstanding catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 % and spatio-temporal controllable abilities are also found within this nano-carrier. Furthermore, HAZD performed good antitumor ability in vivo with the comprehensive effects of photothermal/ chemical dynamic/ chemotherapy. The tumor growth inhibition value is 97.1 % within 12 days, indicating its great potential in multi-modal synergistic cancer therapy. STATEMENT OF SIGNIFICANCE: Cancer remains one of the major culprits that seriously harm human health currently. With the development of materials and nanotechnology, great improvements have been made in multimodal anti-tumor strategies. However, temporal- and spatial-controllable multi-modal synergistic nanocarriers are urgently awaited for efficient and low-toxicity tumor therapy. This article proposes a spatio-temporally controllable three-modal anti-tumor strategy and designs an anti-tumor drug delivery system based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), which shows acid-responsive release characteristics, catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 %, as well as spatio-temporal controllable abilities. Moreover, it demonstrates outstanding anti-tumor ability, with a tumor growth inhibition value of 97.1 % within 12 days, revealing its significant potential for future personalized and precise anti-tumor treatments.

Sniping Cancer Stem Cells with Nanomaterials.

Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.

Synergistic therapeutic effect of nanomotors triggered by Near-infrared light and acidic conditions of tumor.

Due to the complexity of tumors, multimodal therapy for them has always been of concern to researchers. How to design a multifunctional drug nanoplatform with cascade effect and capable of responding to specific stimuli in the tumor microenvironment is the key to achieve efficient multimodal synergistic therapy of cancer. Here, we prepare a kind of GNRs@SiO2@PDA-CuO2-l-Arg (GSPRs-CL) nanomotors for systematic treatment of tumor. First, under near-infrared (NIR) irradiation, GSPRs-CL can generate heat and exhibit excellent photothermal therapy effect. Then under acidic conditions, CuO2 can be decomposed to release Cu2+ and generate H2O2, which not only complemented the limited endogenous H2O2 in cells, but also further triggered Fenton-like reaction, converting H2O2 into •OH to kill cancer cells, thereby achieving chemodynamic therapy. Furthermore, both endogenous and exogenous H2O2 can release nitric oxide (NO) in response to the occurrence of l-Arg of nanomotors to enhance gas therapy. In addition, as a dual-mode drive, NIR laser and NO can promote the penetration ability of nanomotors at tumor sites. The experimental results in vivo show that the drug nanoplatform had good biosafety and significant tumor killing effect triggered by NIR light and acidic conditions of tumor. It provide a promising strategy for the development of advanced drug nanoplatform for cancer therapy.

Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling.

Rationale: Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. The management of aggressive TNBC remains a formidable challenge. Tumor microenvironment (TME), with the unique features, which can serve as the "soil" for the growth and survival of tumor cells (the "seeds"), plays an important regulatory role in the occurrence, proliferation and metastasis of tumors. Catalytic tumor therapy, which can destroy the homeostasis of TME, affect the occurrence and progress of tumors in an all-round way and further magnify chemotherapy, is a quite potential tactic for TNBC-treatment. Methods: Herein, accurate programmed multifunctional cascade nano-missiles (GOx+L-Arg-NM/PTX-NM) composed of novel intelligent all-in-one "nano-rocket" (the drug delivery system) and "ammunitions" (the therapeutic agents) are innovatively constructed by mimicking the functionalities of military precision-guided missiles. Ammunitions can be precisely and effectively transported to the core region of TNBC (the "battlefield") by organic modification on the surface of nano-rocket via chemical means. Once successfully internalized by TNBC cells, the nano-missiles can automatically trigger relevant cascade reactions without external stimulation, prominently disrupt the homeostasis of TME, and produce a "bomb-like" attack on tumors, further promoting the chemotherapy. Results: Both in vitro and in vivo investigations indicated that the innovative nano-missiles could deliver ammunitions to the core area of TNBC to the utmost extent, dramatically ablate tumor and restrain tumor metastasis via orchestrated multimodal synergistic starvation/oxidation/gas/chemotherapy. Conclusion: The well-designed multifunctional nano-missiles may emerge as a new paradigm to suppress the malignant proliferation and metastasis of TNBC, offering a promising approach for the next generation cancer therapy.

Tumor Microenvironment-Activatable Cyclic Cascade Reaction to Reinforce Multimodal Combination Therapy by Destroying the Extracellular Matrix.

The optimal therapy effect of tumors is frequently restricted by the dense extracellular matrix (ECM) and anoxia. Herein, an intelligent BPNs-Arg-GOx@MnO2 (BAGM) nanozyme is innovatively designed as a multimodal synergistic therapeutic paradigm that possesses both nitric oxide (NO) self-supplying and ECM degradation properties to reinforce the therapy effect by a tumor microenvironment (TME)-activatable cyclic cascade catalytic reaction. This theranostic nanoplatform is constructed by using polyethyleneimine-modified black phosphorus nanosheets as a "fishnet" to attach l-Arginine (l-Arg) and glucose oxidase (GOx) and then depositing mini-sized MnO2 nanosheets (MNs) on the surface by a facile situ biomineralization method. As an intelligent "switch", the MNs can effectively trigger the cascade reaction by disintegrating intracellular H2O2 to release O2. Then, the conjugated GOx can utilize O2 production to catalyze intracellular glucose to generate H2O2, which not only starves the tumor cells but also promotes oxidation of l-Arg to NO. Thereafter, matrix metalloproteinases will be activated by NO production to degrade the dense ECM and transform matrix collagen into a loose state. In turn, a loose ECM can enhance the accumulation of the BAGM nanozyme and thereby reinforce synergistic photothermal therapy/starvation therapy/NO gas therapy. Both in vitro and in vivo results indicate that the TME-tunable BAGM therapeutic nanoplatform with cascade anticancer property and satisfactory biosecurity shows potential in nanomedicine.