Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade.

Lung cancer brain metastasis (LCBM) poses a significant clinical challenge due to acquired resistance to tyrosine kinase inhibitor (TKI) treatment. To elucidate its underlying mechanisms, we employed single-cell RNA sequencing analysis on surgically obtained LCBM samples with diverse genetic backgrounds and TKI treatment histories. Our study uncovers that TKI treatment elevates the immune checkpoint CTLA4 expression in T cells, promoting an immune-suppressive microenvironment. This immunomodulation is initiated by tumor-derived HMGB1 in response to TKIs. In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant EGFR mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM.

Cascade Catalytic Nanoparticles Selectively Alkalize Cancerous Lysosomes to Suppress Cancer Progression and Metastasis.

Lysosomes are critical in modulating the progression and metastasis for various cancers. There is currently an unmet need for lysosomal alkalizers that can selectively and safely alter the pH and inhibit the function of cancer lysosomes. Here an effective, selective, and safe lysosomal alkalizer is reported that can inhibit autophagy and suppress tumors in mice. The lysosomal alkalizer consists of an iron oxide core that generates hydroxyl radicals (•OH) in the presence of excessive H+ and hydrogen peroxide inside cancer lysosomes and cerium oxide satellites that capture and convert •OH into hydroxide ions. Alkalized lysosomes, which display impaired enzyme activity and autophagy, lead to cancer cell apoptosis. It is shown that the alkalizer effectively inhibits both local and systemic tumor growth and metastasis in mice. This work demonstrates that the intrinsic properties of nanoparticles can be harnessed to build effective lysosomal alkalizers that are both selective and safe.

Unraveling mitochondria-targeting reactive oxygen species modulation and their implementations in cancer therapy by nanomaterials.

Functional subcellular organelle mitochondria are emerging as a crucial player and driver of cancer. For maintaining the sites of cellular respiration, mitochondria experience production, and accumulation of reactive oxygen species (ROS) underlying oxidative damage in electron transport chain carriers. Precision medicine targeting mitochondria can change nutrient availability and redox homeostasis in cancer cells, which might represent a promising strategy for suppressing tumor growth. Herein, this review highlights how the modification capable of manipulating nanomaterials for ROS generation strategies can influence or compensate the state of mitochondrial redox homeostasis. We propose foresight to guide research and innovation with an overview of seminal work and discuss future challenges and our perspective on the commercialization of novel mitochondria-targeting agents.

Defect self-assembly of metal-organic framework triggers ferroptosis to overcome resistance.

The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours. Ferroptosis, resulting from the iron-dependent accumulation of lipid peroxides, has the potential to reverse multidrug resistance. However, simultaneous delivery of the iron sources, ferroptosis inducers, drugs, and enhanced circulation carriers within matrices remains a significant challenge. Herein, we designed and fabricated a defect self-assembly of metal-organic framework (MOF)-red blood cell (RBC) membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer. Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron (III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process. The RBC membrane could camouflage the nanoplatform for longer circulation. Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione, amplify the reactive oxidative species oxidative stress, and enable remarkable anticancer properties. Our work provides an alternative strategy for overcoming multidrug resistance, which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P-glycoprotein protein expression by ferroptosis. This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.

Simvastatin induced ferroptosis for triple-negative breast cancer therapy.

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.

Nano-delivery systems focused on tumor microenvironment regulation and biomimetic strategies for treatment of breast cancer metastasis.

Breast cancer metastasis and recurrence accounts for vast majority of breast cancer-induced mortality. Tumor microenvironment (TME) plays an important role at each step of metastasis, evasion of immunosurveillance, and therapeutic resistance. Consequently, TME-targeting alternatives to traditional therapies focused on breast cancer cells are gaining increasing attention. These new therapies involve the use of tumor cells, and key TME components or secreted bioactive molecules as therapeutic targets, alone or in combination. Recently, TME-related nanoparticles have been developed to deliver various agents, such as bioactive ingredients extracted from natural sources or chemotherapeutic agents, genes, proteins, small interfering RNAs, and vaccines; they have shown great therapeutic potential against breast cancer metastasis. Among various types of nanoparticles, biomimetic nanovesicles are a promising means of addressing the limitations of conventional nanocarriers. This review highlights various nanoparticles related to or mediated by TME according to the key TME components responsible for metastasis. Furthermore, TME-related biomimetic nanoparticles against breast cancer metastasis have garnered attention owing to their promising efficiency, especially in payload delivery and therapeutic action. Here, we summarize recent representative studies on nanoparticles related to cancer-associated fibroblasts, extracellular matrix, endothelial cells, angiogenesis, and immune cells, as well as advanced biomimetic nanoparticles. Future challenges and opportunities in the field are also discussed.

Dihydroartemisinin-Loaded Magnetic Nanoparticles for Enhanced Chemodynamic Therapy.

Recently, chemodynamic therapy (CDT) has represented a new approach for cancer treatment with low toxicity and side effects. Nonetheless, it has been a challenge to improve the therapeutic effect through increasing the amount of reactive oxygen species (ROS). Herein, we increased the amount of ROS agents in the Fenton-like reaction by loading dihydroartemisinin (DHA) which was an artemisinin (ART) derivative containing peroxide groups, into magnetic nanoparticles (MNP), thereby improving the therapeutic effect of CDT. Blank MNP were almost non-cytotoxic, whereas three MNP loading ART-based drugs, MNP-ART, MNP-DHA, and MNP-artesunate (MNP-AS), all showed significant killing effect on breast cancer cells (MCF-7 cells), in which MNP-DHA were the most potent. What's more, the MNP-DHA showed high toxicity to drug-resistant breast cancer cells (MCF-7/ADR cells), demonstrating its ability to overcome multidrug resistance (MDR). The study revealed that MNP could produce ferrous ions under the acidic condition of tumor microenvironment, which catalyzed DHA to produce large amounts of ROS, leading to cell death. Further experiments also showed that the MNP-DHA had significant inhibitory effect on another two aggressive breast cancer cell lines (MDA-MB-231 and MDA-MB-453 cells), which indicated that the great potential of MNP-DHA for the treatment of intractable breast cancers.

Biomimetic Mesoporous Silica Nanoparticles for Enhanced Blood Circulation and Cancer Therapy.

The biomimetic cell membrane camouflaged approach provides numerous opportunities in designing therapeutic platforms for various biomedical applications. It is necessary to understand the engineering of physicochemical properties on materials' surfaces for target biological functions to develop the next-generation anticancer nanomedicines. Herein, we envelope mesoporous silica nanoparticles (MSNs) with red blood cell (RBC) membrane ghosts to obtain MSN@RBC, which possesses significantly stronger physiological stability and longer circulation time than bare MSNs. The surface functionalization of the core material is a critical design parameter for RBC membrane coating efficiency. Therefore, various surface functionalization (-COOH, -SH, -NH2) modifications were performed on MSNs. Compared with other groups, MSN-COOH possessed a better RBC membrane coating efficiency. Then, MSN-COOH of different particle sizes were coated by RBC-derived vesicle membranes. The results indicated that smaller types were able to last longer in blood circulation and accumulate more in target sites than the larger ones. Overall, MSN-ICG@RBC with surface functionalization of -COOH and optimized particle size of 60 nm led to efficient imaging-guided photothermal cancer treatment and could be potentially appealing to actual clinical applications in the future.

Metal-Organic Frameworks-Derived Carbon Nanoparticles for Photoacoustic Imaging-Guided Photothermal/Photodynamic Combined Therapy.

Combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has become a promising cancer treatment in recent years. However, their applications are limited by complex synthetic protocols and low efficacy. Hence, optimizing experimental approach and improving the efficiency of phototherapy is the current research focus. In this work, various pyrolysis temperatures and sizes of zeolitic imidazolate framework-8 (ZIF-8) derived carbon nanoparticles (ZCNs) are obtained by a simple direct pyrolysis of the ZIF-8 nanoparticles. Meanwhile, the ZCNs can be used as photothermal agents and photosensitizers to produce heat and reactive oxygen species simultaneously upon near-infrared laser irradiation. Moreover, it is observed that the phototherapy effects and photoacoustic (PA) signal of ZCNs could be enhanced with the increase in the nanoparticle size. Subsequently, guided by PA imaging, the therapeutic effect of ZCNs is investigated on a small animal model, where tumors are entirely eliminated with minimal side effect, demonstrating the high efficacy of the larger size of ZCNs through combination of PTT and PDT. Therefore, it is expected that the ZCN is a simple and highly effective phototherapeutic platform for oncotherapy, and the concept of size-dependent enhanced behavior of phototherapy and PA imaging will be very useful in the development of nanomaterials for cancer therapy.

Blocking Autophagic Flux Enhances Iron Oxide Nanoparticle Photothermal Therapeutic Efficiency in Cancer Treatment.

Autophagy is a conservative eukaryotic pathway which plays a crucial role in maintaining cellular homeostasis, and dysfunction of autophagy is usually associated with pathological conditions. Recently, emerging reports have stressed that various types of nanomaterials and therapeutic approaches interfere with cellular autophagy process, which has brought up concerns to their future biomedical applications. Here, we present a study elaborating the relationships between autophagy and iron oxide nanoparticle (IONP)-mediated photothermal therapy in cancer treatment. Our results reveal that IONP photothermal effect could lead to autophagy induction in cancerous MCF-7 cells in a laser dose-dependent manner, and the inhibition of autophagy would enhance the photothermal cell killing by increasing cell apoptosis. In an MCF-7 xenograft model, cotreatment of autophagy inhibitor and IONP under laser exposure could promote the tumor inhibition rate from 43.26 to 68.56%, and the tumor immunohistochemistry assay of microtubule-associated protein 1-light chain 3 (LC3) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling also demonstrate augmentation in both autophagosomes accumulation and apoptosis in vivo. This work helps us to better understand the regulation of autophagy during IONP-mediated photothermal therapy and provides us with a potential combination therapeutic approach of autophagy modulators and photothermal agents.

Plant Protein-Directed Synthesis of Luminescent Gold Nanocluster Hybrids for Tumor Imaging.

Nowadays, fluorescence detection has emerged as one of the most frequently used noninvasive biosensing methods to selectively monitor biological processes within living systems. Among fluorescent nanoparticles (NPs), gold nanoclusters (AuNCs) have been intensively studied because of their intrinsic fluorescence and their endowed biocompatible surface. Herein, we selected an abundant, low-cost, and sustainable plant protein, the pea protein isolate (PPI), for its excellent biocompatibility, biodegradability, and nonallergenic character to be employed as both a reducing and stabilizing agent to facilely produce AuNCs exhibiting a strong red fluorescence. Afterward, the formed AuNCs/PPI mixture was able to self-assemble into NPs (AuNCs/PPI NPs) with the size of about 100 nm simply through a dialyzing process. Taking advantage from the protein nature of PPI, AuNCs/PPI NPs demonstrate both excellent biocompatibility and colloidal stability. Moreover, AuNCs/PPI NPs showed a great capability when employed as a bioimaging probe for both in vitro and in vivo imaging. Finally, AuNCs/PPI NPs were coated with red blood cell (RBC) membranes to improve their blood circulation property and enhance their tumor enrichment ability to meet the requirement for practical use. Results convincingly show that such super NPs (RBC-coated AuNCs/PPI NPs) were able to successfully locate tumor in vivowith an excellent imaging capability, which provides a new strategy for bioimaging with fluorescent NPs.

Red blood cell membrane-camouflaged melanin nanoparticles for enhanced photothermal therapy.

Photothermal therapy (PTT) has represented a promising noninvasive approach for cancer treatment in recent years. However, there still remain challenges in developing non-toxic and biodegradable biomaterials with high photothermal efficiency in vivo. Herein, we explored natural melanin nanoparticles extracted from living cuttlefish as effective photothermal agents and developed red blood cell (RBC) membrane-camouflaged melanin (Melanin@RBC) nanoparticles as a platform for in vivo antitumor PTT. The as-obtained natural melanin nanoparticles demonstrated strong absorption at NIR region, higher photothermal conversion efficiency (∼40%) than synthesized melanin-like polydopamine nanoparticles (∼29%), as well as favorable biocompatibility and biodegradability. It was shown that RBC membrane coating on melanin nanoparticles retained their excellent photothermal property, enhanced their blood retention and effectively improved their accumulation at tumor sites. With the guidance of their inherited photoacoustic imaging capability, optimal accumulation of Melanin@RBC at tumors was achieved around 4 h post intravenous injection. Upon irradiation by an 808-nm laser, the developed Melanin@RBC nanoparticles exhibited significantly higher PTT efficacy than that of bare melanin nanoparticles in A549 tumor-bearing mice. Given that both melanin nanoparticles and RBC membrane are native biomaterials, the developed Melanin@RBC platform could have great potential in clinics for anticancer PTT.

Nuclear-Targeted Multifunctional Magnetic Nanoparticles for Photothermal Therapy.

The pursuit of multifunctional, innovative, more efficient, and safer cancer treatment has gained increasing interest in the research of preclinical nanoparticle-mediated photothermal therapy (PTT). Cell nucleus is recognized as the ideal target for cancer treatment because it plays a central role in genetic information and the transcription machinery reside. In this work, an efficient nuclear-targeted PTT strategy is proposed using transferrin and TAT peptide (TAT: YGRKKRRQRRR) conjugated monodisperse magnetic nanoparticles, which can be readily functionalized and stabilized for potential diagnostic and therapeutic applications. The monodisperse magnetic nanoparticles exhibit high photothermal conversion efficiency (≈37%) and considerable photothermal stability. They also show a high magnetization value and transverse relaxivity (207.1 mm-1 s-1 ), which could be applied for magnetic resonance imaging. The monodisperse magnetic nanoparticles conjugated with TAT peptides can efficiently target the nucleus and achieve the imaging-guided function, efficient cancer cells killing ability. Therefore, this work may present a practicable strategy to develop subcellular organelle targeted PTT agents for simultaneous cancer targeting, imaging, and therapy.

New Application of Old Material: Chinese Traditional Ink for Photothermal Therapy of Metastatic Lymph Nodes.

Finding a simple and effective strategy to eliminate tumor metastatic lymph nodes is highly desired in clinical tumor treatment. Herein, we reported a Chinese traditional ink (Hu-ink)-based treatment for photothermal therapy (PTT) of tumor metastatic lymph nodes. By simple dilution, stable Chinese traditional ink dispersion was obtained, which presents excellent photothermal effect because of its high absorption in near-infrared (NIR) region. Meanwhile, as revealed by staining and photoacoustic imaging, Hu-ink could transfer to nearby lymph nodes after directly injected into the primary tumors. Under the guidance of dual-modality mapping, the metastatic sentinel lymph nodes could be subsequently eliminated by NIR irradiation. The good biocompatibility of Hu-ink has also been verified by a series of experiments. Therefore, the Hu-ink-based treatment exhibits great potential for PTT of tumor metastatic lymph nodes in future clinical practice.

Mitochondria-Targeting Magnetic Composite Nanoparticles for Enhanced Phototherapy of Cancer.

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual-modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria-targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria-targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.

Synthesis of CaCO3 Nanobelts for Drug Delivery in Cancer Therapy.

Nanobelt carriers have demonstrated some advantages such as good biocompatibility, biodegradability, and strain-accommodating properties. We prepared an optimized nanobelt carrier formulation for drug (etoposide) as an oral delivery system and estimated the potential of calcium carbonate (CaCO3) nanobelts. The nanobelts were prepared by the method of binary solvent approach and were characterized by transmission electron microscope (TEM), scanning electron microscopy (SEM), and ultraviolet-visible (UV-vis) spectra. MTT (3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide) assay test exhibited that etoposide-loaded calcium carbonate nanobelts (ECCNBs) showed a higher cell kill ratio against SGC-7901 cells compared with free drug. The apoptosis test and cell cycle test analysis revealed that etoposide entrapped in calcium carbonate nanobelts (CCNBs) could enhance the delivery efficiencies of drug and improved inhibition effect. The present findings demonstrated that ECCNBs might induce cell cycle arrest at G2/M phase and cell apoptosis in a p53-related manner. It can be foreseen that CCNBs are a promising drug carrier to store the anti-cancer drug for cancer therapy and drug delivery.

Preparation of hierarchical mesoporous CaCO3 by a facile binary solvent approach as anticancer drug carrier for etoposide.

To develop a nontoxic system for targeting therapy, a new highly ordered hierarchical mesoporous calcium carbonate nanospheres (CCNSs) as small drug carriers has been synthesized by a mild and facile binary solvent approach under the normal temperature and pressure. The hierarchical structure by multistage self-assembled strategy was confirmed by TEM and SEM, and a possible formation process was proposed. Due to the large fraction of voids inside the nanospheres which provides space for physical absorption, the CCNSs can stably encapsulate the anticancer drug etoposide with the drug loading efficiency as high as 39.7 wt.%, and etoposide-loaded CCNS (ECCNS) nanoparticles can dispersed well in the cell culture. Besides, the drug release behavior investigated at three different pH values showed that the release of etoposide from CCNSs was pH-sensitive. MTT assay showed that compared with free etoposide, ECCNSs exhibited a higher cell inhibition ratio against SGC-7901 cells and also decreased the toxicity of etoposide to HEK 293 T cells. The CLSM image showed that ECCNSs exhibited a high efficiency of intracellular delivery, especially in nuclear invasion. The apoptosis test revealed that etoposide entrapped in CCNSs could enhance the delivery efficiencies of drug to achieve an improved inhibition effect on cell growth. These results clearly implied that the CCNSs are a promising drug delivery system for etoposide in cancer therapy.