Tumor Targeting Research Articles

Melanoma extracellular vesicles membrane coated nanoparticles as targeted delivery carriers for tumor and lungs.

Targeting is the most challenging problem to solve for drug delivery systems. Despite the use of targeting units such as antibodies, peptides and proteins to increase their penetration in tumors the amount of therapeutics that reach the target is very small, even with the use of nanoparticles (NPs). Nature has solved the selectivity problem using a combination of proteins and lipids that are exposed on the cell membranes and are able to recognize specific tissues as demonstrated by cancer metastasis. Extracellular vesicles (EVs) have a similar ability in target only certain organs or to return to their original cells, showing home behavior. Here we report a strategy inspired by nature, using a combination of NPs and the targeting cell membranes of EVs. We implement the EV membranes, extracted by the EVs produced by melanoma B16-BL6 cells, as a coating of organosilica porous particles with the aim of targeting tumors and lung metastasis, while avoiding systemic effects and accumulation of the NPs in undesired organs. The tissue-specific fingerprint provided by the EVs-derived membranes from melanoma cells provides preferential uptake into the tumor and selective targeting of lungs. The ability of the EVs hybrid systems to behave as the natural EVs was demonstrated in vitro and in vivo in two different tumor models. As a proof of concept, the loading and release of doxorubicin, was investigated and its accumulation demonstrated in the expected tissues.

The second phase of tumor invasion driven by immune cells: A study on doxorubicin-loaded PLG nanoparticles.

Poly(lactide-co-glycolide) (PLG) nanoparticles loaded with doxorubicin have reached phase-I clinical trials for treating advanced solid tumors. This study explores cell hitchhiking, where nanoparticles associate with blood cells and investigates the impact on pharmacokinetics and tumor migration. Previous findings highlighted the early post-injection phase dominated by nonspecific nanoparticle-cell interactions and burst release. In contrast, this study examines the subsequent phase of tumor invasion, emphasizing the role of immune cells, mostly neutrophils, in redistributing the carrier to the tumor site via blood cell hitchhiking. We provide a detailed investigation of nanoparticle extravasation kinetics and mechanisms, showing qualitative and quantitative evidence of increased nanoparticle association with immune cells over time. By 30 min post-injection, approximately 15 % of monocytes and 15-19 % of neutrophils tested positive for nanoparticles, with significant differences observed between ex vivo and in vivo experiments, and between healthy and tumor-bearing animals. This study underscores the ambiguous role of immune cell-mediated tumor targeting. While the total accumulation of the carrier rises, this fraction is partially trapped in immune cells without any chance to escape.

Albumin-Energized NIR-II Cyanine Dye for Fluorescence/Photoacoustic/Photothermal Multi-Modality Imaging-Guided Tumor Homologous Targeting Photothermal Therapy.

Endowing cyanine dyes with hydrophilicity, long blood circulation, tumor targeting, and robust therapeutic efficacy in the second near-infrared (NIR-II) window is challenging for cancer treatment. Herein, we develop cancer cell membrane-coated albumin-NIR-II cyanine dye assemblies, denoted as LZ-1105@HAm, to optimize the photophysical properties of cyanine dyes in aqueous solution for NIR-II fluorescence (FL)/photoacoustic (PA)/photothermal (PT) multimodality imaging-guided tumor homologous targeting photothermal therapy. LZ-1105@HAm exhibits good hydrophilicity, extends the half-life of blood circulation from 0.634 ± 0.058 to 1.919 ± 0.107 h, enhances NIR-II FL/PA/PT imaging capabilities in vitro and in vivo, and improves photothermal conversion efficiency from 34.6% to 45.4%. Additionally, the cell membrane coating confers the assemblies with tumor-specific targeting capability, increasing tumor accumulation and enabling efficient photothermal tumor ablation. Upon 1064 nm laser irradiation, LZ-1105@HAm demonstrates significantly improved therapeutic efficacy. This research provides a strategy for constructing cyanine dye-based nanotheranostics with potential clinical application prospects.

Phase-separating Pt(IV)-graft-glycopeptides sequentially sensing pH and redox for deep tumor penetration and targeting chemotherapy.

Active-targeting nanomedicines have been widely employed in cancer treatment for increasing therapeutic index. However, the limited permeability caused by the binding site barrier (BSB) and size hindrances compromises their clinical antitumor efficacy in patients. Herein, learning from the liquid-liquid phase separation (LLPS) of bio-macromolecules, we report phase-separating glycopeptides (HEP) from polyhistidine (PHis) grafted hyaluronic acid (HA), which can sense the tumor extracellular pH and concomitantly overcome size and BSB dilemmas for enhanced tumor penetration. HEP aggregates into nanodroplets in solution at neutral pH. Upon reaching the acidic extracellular environment of tumors, the pH-responsive PHis triggers a phase separation, converting the coacervate nanodroplets into monomeric glycopeptides. This enables HEP conjugated with the platinum prodrug (HEPPt) to deeply penetrate into tumors by overcoming the BSB effect arising from the interaction between nanodroplets and cluster of differentiation 44 (CD44), as well as resolving the size challenges. Moreover, HEPPt in monomeric states exhibits promoted cellular uptake after pH-triggered phase separation, attributed to the transmembrane effect of exposed PHis. Subsequently, the rapid release of Pt(II), triggered by tumor intracellular reducing environment, exerts excellent antitumor activity. The phase-separating glycopeptides represent a promising platform for improving tumor penetration and intracellular delivery of therapeutic agents.

Navigating liver cancer: Precision targeting for enhanced treatment outcomes.

Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Applications of cell penetrating peptide-based drug delivery system in immunotherapy

Cell penetrating peptides (CPPs) are usually positive charged peptides and have good cell membrane permeability. Meanwhile, CPPs are facile to synthesize, and can be functionalized to satisfy different demands, such as cyclization, incorporating unnatural amino acids, and lipid conjugation. These properties have made them as efficient drug-delivery tools to deliver therapeutic molecules to cells and tissues in a nontoxic manner, including small molecules, DNA, siRNA, therapeutic proteins and other various nanoparticles. However, the poor serum stability and low tumor targeting ability also hindered their broad application. Besides, inappropriate chemical modification can lead to membrane disruption and nonspecific toxicity. In this paper, we first reviewed recent advances in the CPP applications for cancer therapy via covalent or non-covalent manners. We carefully analyzed the advantages and disadvantages of each CPP modifications for drug delivery. Then, we concluded the recent progress of their clinical trials for different diseases. Finally, we discussed the challenges and opportunities CPPs met to translate into clinical applications. This review presented a new insight into CPPs for drug delivery, which could provide advice on the design of clinically effective systemic delivery systems using CPPs.

Mannose functionalized small molecule nanodrug self-assembled from amphiphilic prodrug connected by disulfide bonds for synergistic cancer chemotherapy and photodynamic/photothermal therapy.

Compared to conventional nanocarrier-based drug delivery technology, small-molecule-assembled nanomaterials provide various advantages, including higher drug loading efficiency, lower excipient-related toxicity, and a simpler formulation process. Our research constructed a mannonse-modified small-molecule-assembled nanodrug for synergistic photodynamic/chemotherapy against A549 cancer cells. The hydrophobic hypoxic-activated agent tirapazamine (TPZ) and a hydrophilic fluorescence probe Cyanine 3 (Cy3) constitute this amphiphilic prodrug via a glutathione (GSH)-responsive linkage, which could self-assemble into stable nanoparticles (NPs) and encapsulate a newly synthesized photosensitizer (SeBDP). To enhance the tumor targeting capability, we introduced a tumor-targeted nanodrug SeBDP@TPZ-S-S-Cy/Man NPs by co-assembling mannose-modified lipid (DSPE-PEG-Man). The GSH-responsive linkage of TPZ-S-S-Cy can be rapidly cleaved by GSH to release the therapeutic agents and fluorescent molecule. The released SeBDP generate reactive oxygen species (ROS) to specifically kill cancer cells and elevate hypoxia, thereby enhancing the cytotoxicity of TPZ. SeBDP@TPZ-S-S-Cy/Man NPs exhibited high selectivity and efficiency for in vivo combination therapy without adverse effects to normal tissues. Our findings demonstrate that SeBDP@TPZ-S-S-Cy/Man NPs have great potential for enhancing cancer treatment both in vitro and in vivo by combining an oxygen depletion prodrug with a hypoxia-activated antitumor agent. Thus, the GSH-sensitive self-assembled nanodrug from an amphiphilic hypoxia-activated prodrug, could serve as a potential drug carrier in targeted synergistic cancer therapy.

Hyaluronic acid-mediated targeted nano-modulators for activation of pyroptosis for cancer therapy through multichannel regulation of Ca2+ overload.

Calcium-based nanomaterials-mediated Ca2+ overload-induced pyroptosis and its application in tumor therapy have received considerable attention. However, the calcium buffering capacity of tumor cells can maintain mitochondrial calcium homeostasis, so it is important to effectively disrupt this homeostasis to activate pyroptosis. Here, a nano-modulator CUR@CaCO3-PArg@HA (CCAH) was developed to regulate calcium overload in multiple channels and activate pyroptosis. Hyaluronic acid (HA)-coated nano-modulators achieve tumor targeting, and under the weakly acidic conditions of the tumor microenvironment (TME), CaCO3 nanoparticles rapidly release curcumin (CUR), inhibit the outflow of intracellular Ca2+, and release exogenous Ca2+. Meanwhile, poly-L-arginine (PArg) reacts with reactive oxygen species (ROS) generated by mitochondrial imbalance, releasing nitric oxide (NO) and stimulating the endoplasmic reticulum to release endogenous Ca2+. The combined action of endogenous and exogenous Ca2+ effectively activates caspase-1, which cleaves gasdermin-D (GSDMD) to produce the active N-terminus (GSDMD-N), effectively activating pyroptosis. Notably, the generated ROS and NO can also generate more oxidizing ONOO-, further exacerbating the imbalance in mitochondrial homeostasis. This work demonstrates that simultaneous modulation of exogenous and endogenous Ca2+ can disrupt mitochondrial Ca2+ homeostasis and effectively activate pyroptosis to treat tumors, which is expected to promote the progression of cancer treatment in the future.

Self-assembly of multi-arm star PEG containing TXA9 into nanoparticle for the efficient chemotherapy of NSCLC.

TXA9, a cardiac glycoside isolated from the root of Streptocaulon juventas (Lour.) Merr., with better therapeutic effect in vitro on non-small cell lung cancer (NSCLC) than cisplatin and has no toxic side effects on the body. However, poor water solubility and rapid metabolism limited its clinical application. Multi-arm star PEG have many advantages over linear PEG, such as high drug loading due to more terminals and better anti-hemodilution ability, which have become popular carriers for drug delivery. In this study, to improve the efficacy of TXA9, 6/8armPEGn-Glycine Carbamate (Gly) (n = 10, 20, and 40kDa) were used as carriers to prepare star PEG-TXA9 conjugates. The particle size and zeta potential of six prodrug NPs for effective tumor targeting, with suitable drug loading, and good water solubility. Compared with free TXA9, 6/8APGn-T NPs had more significant anti-tumor effects in vitro. Since the multi-arm star PEG formed an "umbrella" structure on the surface of NPs, the 8APG40k-T NPs with the best pharmacokinetic properties increased half-life of TXA9 about 60 times in vivo. In addition, the arm numbers and molecular weight of multi-arm star PEGs significantly influenced the in vivo destiny of prodrugs. In vivo experiments showed that the same dose of 8APG40k-T NPs increased the tumor inhibition rate about 3.56 or 1.22 times compared with TXA9 or cisplatin, and had good biocompatibility. This study provides a simple but effective strategy to solve the challenges caused by the poor water solubility and short half-life of TXA9 for developing the TXA9 as a safe and effective drug against NSCLC.

Homotypic membrane-camouflaged camptothecin nanorods combining photothermal and chemotherapy for synergistic antitumor therapy.

Chemotherapy hardly achieves satisfactory therapeutic efficacy owing to the widely occurred adverse effects and drug tolerance, and the extensively investigated delivery systems suffer from complicated synthesis, low drug loading and less efficient tumor accumulation. Herein, we developed rod-shape nanocrystals to address challenges in the circulation stability, tumor targeting and therapeutic efficacy of camptothecin (CPT), a mainstay of treatments for various cancers. CPT nanorods (CNR) were coated with polydopamine (PDA) to achieve combinational chemo- and photothermal therapies (PTT) and then wrapped with cell membrane (CM) from homotypic tumor cells to obtain CNR@PDA-CM. CNR@PDA-CM retained the membrane proteins presented on 4T1 cell surface, holding the potential to decrease phagocytic uptake and selectively accumulate in tumor cells. The integration of rod shape and CM wrapping prolongs blood circulation, and CNR@PDA-CM achieves 73-fold longer terminal half-life and nearly 5-fold higher tumor accumulation than free CPT after intravenous injection. When reaching tumor sites, PDA-mediated photothermal effect accelerates CPT release and enhances drug permeability in tumors. The combination of PTT and CPT-based chemotherapy produce robust and synergistic therapeutic outcome in metastatic breast cancer, with almost compete inhibition of tumor growth and 100% mouse survival at the end of experiment. Thus, this study demonstrates a concise design of CNRs with high drug loading, desirable homotypic targeting, synergistic antitumor efficacy to potentially provide new insight for effective treatment of metastatic cancers.

A Powerful Tumor Catalytic Therapy by an Enzyme-Nanozyme Cascade Catalysis (ENCAT) System.

Complexity of tumor and its microenvironment as obstacles often restrict traditional tumor therapies. Enzyme/nanozyme-mediated catalytic therapy has been emerged, but the efficacy of single catalytic therapy is still moderate. Inspired by the concepts of catalytic and synergetic therapy, an enzyme-nanozyme cascade catalysis (ENCAT)-enhanced tumor therapy is developed. First, metal-organic framework (MOF) PCN222-Mn (PM) and glucose oxidase (GOx) are chosen as nanozyme and natural enzyme, respectively. Then two assembled together to form enzyme-nanozyme complex PCN222-Mn@GOx (PMG). To achieve tumor targeting and GOx protection, hyaluronic acid (HA) is modified on PMG to obtain PCN222-Mn@GOx/HA (PMGH). Both cellular and animal studies demonstrate a cascade catalysis-enhanced tumor therapy by PMGH. Specifically, a cascade catalysis-enhanced PDT is achieved based on enzyme-nanozyme mediated cascade-catalyzed O2 generation; an enhanced synergistic therapy is demonstrated by combining PM-mediated PDT, GOx-mediated starvation therapy, and activated/promoted immunotherapy together. Additionally, the designed tumor catalytic therapy is explored in a tumor bearing mouse model, where it exhibits powerful anti-tumor effects against both primary and metastatic tumors. This strategy has the potential to broaden tumor therapeutic approaches.

Nanoparticle innovations in targeted cancer therapy: advancements in antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have emerged as a promising strategy in targeted cancer therapy, enabling the precise delivery of cytotoxic agents to tumor sites while minimizing systemic toxicity. However, traditional ADCs face significant limitations, including restricted drug loading capacity, where an optimal drug-to-antibody ratio (DAR) is crucial; low DARs may lead to insufficient potency, while high DARs can cause rapid clearance and increased toxicity. Additionally, ADCs often suffer from instability in circulation due to the potential for premature release of cytotoxic agents, resulting in off-target effects and reduced therapeutic efficacy. Furthermore, their large size can impede adequate penetration into solid tumors, particularly in heterogeneous environments with varying antigen expressions. This review explores the innovative use of nanoparticles as carriers for ADCs, which offers a multifaceted approach to enhance therapeutic efficacy. By leveraging the unique properties of nanoparticles, such as their small size and ability to exploit the enhanced permeability and retention (EPR) effect, researchers can improve drug stability, prolong circulation time, and achieve more effective tumor targeting. Recent studies demonstrate that nanoparticle-encapsulated ADCs can significantly enhance treatment outcomes while reducing off-target effects, as evidenced by improved targeting capabilities and reduced toxicity in preclinical models. Despite the promising advancements, challenges remain, including potential nanoparticle toxicity and manufacturing complexities. This review aims to provide a comprehensive overview of the current research on nanoparticle-encapsulated ADCs. It highlights their potential to transform cancer treatment and offers insights into future directions for optimizing these advanced therapeutic strategies.

Large-capacity DNA vectors based on rolling circle amplification with multivalent aptamers delivery copper sulfide for the synergistic treatment of Cancer through chemo/Photothermal/Chemodynamic therapy in vitro.

Developing multifunctional nanomedicines represents a frontier. We have engineered a high-capacity DNA vector basing rolling circle amplification for the delivery of copper sulfide nanoparticles (CuS NPs) and doxorubicin (DOX), coupled with multivalent aptamers (MA) that precisely target tumors, culminating in a multifunctional nanoplatform (RMAL1Cu@DOX), which combines the chemotherapy (CT)/photothermal therapy (PTT)/chemodynamic therapy (CDT). The vector (RMAL1) boasts exceptional biocompatibility and incorporates multiple copy units, enabling the precise loading of numerous CuS NPs, forming RMAL1Cu which possesses a robust photothermal effect and superior Fenton-like catalytic activity, heralding a project of minimally invasive dual-mode (PTT/CDT) therapy. Furthermore, the abundance of G-C of RMAL1 enabled effective DOX encapsulation through π-π interactions to construct RMAL1Cu@DOX. The MA integrated into RMAL1Cu@DOX is pivotal in enhancing the targeting of tumors and in preventing non-specific release of CuS and DOX, enabling an integrated CT/PTT/CDT. Data indicate that 1nM of RMAL1Cu could load 270nM of DOX with an impressive loading capacity of 77%, and modification with MA, its tumor-targeting ability was amplified by 51-fold and significantly bolstered in vitro imaging outcomes, and the synergistic killing of B16 was as 67.3%. This innovative nanoplatform offers a comprehensive and holistic strategy for the treatment of malignant tumors.

Evaluation of maSSS/maSES-PEG2-RM26 for their potential therapeutic use after labeling with Re-188. Could their [99mTc]Tc-labeled counterparts be used to estimate dosimetry?

BackgroundGastrin releasing peptide receptor (GRPR)-directed radiopharmaceuticals for targeted radionuclide therapy may be a very promising addition in prostate and breast cancer patient management. Aiming to provide a GRPR-targeting theranostic pair, we have utilized the Tc-99m/Re-188 radiometal pair, in combination with two bombesin based antagonists, maSSS-PEG2-RM26 and maSES-PEG2-RM26. The two main aims of the current study were (i) to elucidate the influence of the radiometal-exchange on the biodistribution profile of the two peptides and (ii) to evaluate the feasibility of using the [99mTc]Tc labeled counterparts for the dosimetry estimation for the [188Re]Re-labeled conjugates.ResultsBoth peptides were successfully labeled with Re-188 and evaluated both in vitro and in vivo. In GRPR expressing PC-3 cells, both [188Re]Re-labeled peptides displayed high cellular uptake (8.5 ± 0.1% and 5 ± 0.3% of added activity, respectively), heavily GRPR-driven, while retaining the radioantagonistic profile with slow internalization rates. Both agents demonstrated high receptor affinity when loaded with natRe (7.5 nM and 8 nM, respectively). When tested in vivo in GRPR expressing PC-3 xenografts, both radioantagonists demonstrated high tumor accumulation (6.3 ± 0.5%IA/g and 5 ± 1%IA/g at 1 h pi, respectively), with good retention over time (4 ± 2%IA/g and 3.1 ± 0.1%IA/g at 4 h pi, respectively). In addition, their biodistribution profiles were closely mimicking their [99mTc]Tc-labeled counterparts. Statistically significant lower tumor uptake was found for both conjugates labeled with Tc-99m, which may result in underestimation of the dose delivered to the tumor.ConclusionsAll the results indicate that Tc-99 m could be used for dosimetry evaluation for the two [188Re]Re-labeled radioligands, with minimal alterations in their biodistribution pattern and tumor targeting capabilities.

Thiophene engineering of near-infrared D-π-A nano-photosensitizers for enhanced multiple phototheranostics and inhibition of tumor metastasis.

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) is widely used for cancer treatment because of its non-invasiveness, spatiotemporal controllability, and low side effects. However, the PTT and PDT capabilities of photosensitizers (PSs) compete so it's still a crucial challenge to simultaneously enhance the PDT and PTT capabilities of PSs. In this work, donor-π-acceptor (D-π-A)-based boron dipyrromethene (BODIPY) dyes were developed via molecular engineering and applied for enhanced phototherapy of triple-negative breast cancer. With thiophene engineering and iodine addition, D-π-A BDP dyes possessed a low energy gap between the singlet and triplet states (ΔES1-T1). After the BDP dyes were prepared into nanoparticles (NPs), the BDP4 NPs showed increased generation of type I and II reactive oxygen species (ROS) as well as a high photothermal conversion efficiency (44%). Furthermore, folate (FA)-modified BDP4 NPs achieved high tumor targeting via near-infrared bioimaging. With these advantages, BDP4 NPs with FA achieved total tumor eradication and tumor metastasis suppression via a single injection and 808nm laser irradiation. This work provided a rational design of D-π-A PSs for simultaneously enhancing their photodynamic and photothermal performance, achieving efficient cancer therapy.

Synthesis, Preclinical Evaluation, and First-in-Human Assessment of ICG-PSMA-D5: A PSMA-Targeted Probe for Fluorescence-Guided Surgery of Prostate Cancer.

Precise surgical resection of prostate cancer (PCa) is a significant clinical challenge due to the impact of positive surgical margins on postoperative outcomes. Fluorescence-guided surgery (FGS) enables real-time tumor visualization using fluorescent probes. In this study, we synthesized and evaluated an indocyanine green (ICG)-based PSMA-targeted near-infrared probe, ICG-PSMA-D5, for intraoperative imaging of PCa lesions. Spectroscopic analysis revealed that ICG-PSMA-D5 retained the optical properties of ICG while improving solubility in PBS due to additional carboxyl groups. In vitro assays demonstrated high binding affinity (Ki = 0.39 nM) and minimal cytotoxicity. In vivo studies in tumor-bearing mice showed strong tumor targeting, extended retention at tumor site, and favorable biodistribution, with significant tumor-to-background ratios. The first-in-human study in a patient with localized PCa indicated the probe's potential for real-time, radiation-free surgical guidance. Overall, ICG-PSMA-D5 displayed excellent performance in tumor detection and margin delineation, making it a promising candidate for intraoperative FGS in PCa.

Hybrid Membrane Biomimetic Photothermal Nanorobots for Enhanced Chemodynamic-Chemotherapy-Immunotherapy.

Glioblastoma multiforme (GBM) is a highly invasive and fatal brain tumor with a grim prognosis, where current treatment modalities, including postoperative radiotherapy and temozolomide chemotherapy, yield a median survival of only 15 months. The challenges of tumor heterogeneity, drug resistance, and the blood-brain barrier necessitate innovative therapeutic approaches. This study introduces a strategy employing biomimetic magnetic nanorobots encapsulated with hybrid membranes derived from platelets and M1 macrophages to enhance blood-brain barrier penetration and target GBM. The nanorobots encapsulate a polypyrrole/Fe3O4 nanocomplex (PPy@F) for photothermal therapy (PTT) and promote the Fenton reaction of Fe3O4 to generate chemodynamic therapy (CDT). Additionally, temozolomide and PD-L1 antibody (SNTSESF) act as chemotherapy drug and immune checkpoint inhibitor, respectively. The biomimetic design leverages the functional properties of cell membranes to improve the blood residence time and tumor targeting. The integration of PTT and CDT aims to transform "cold" tumors into "hot" tumors, thereby enhancing immunotherapeutic efficacy. This multifaceted approach, PTT, CT, CDT, and immune checkpoint blockade therapy, offers a promising strategy for the treatment of GBM.

MOF-derived intelligent arenobufagin nanocomposites with glucose metabolism inhibition for enhanced bioenergetic therapy and integrated photothermal-chemodynamic-chemotherapy

Bioenergetic therapy based on tumor glucose metabolism is emerging as a promising therapeutic modality. To overcome the poor bioavailability and toxicity of arenobufagin (ArBu), a MOF-derived intelligent nanosystem, ZIAMH, was designed to facilitate energy deprivation by simultaneous interventions of glycolysis, OXPHOS and TCA cycle. Herein, zeolitic imidazolate framework-8 was loaded with ArBu and indocyanine green, encapsulated within metal–phenolic networks for chemodynamic therapy and hyaluronic acid modification for tumor targeting. ZIAMH nanoparticles can release ArBu in the tumor microenvironment for chemtherapy, and ICG enables photothermal therapy under near-infrared laser irradiation. In vitro and in vivo mechanism studies revealed that the ZIAMH nanoplatform downregulated glucose metabolism related genes, resulting in the reduction of energy substances and metabolites in tumors. Additionally, it significantly promoted cell apoptosis by upregulating pro-apoptotic proteins such as Bax, Bax/Bcl-2, cytochrome C. Animal studies have shown that the tumor inhibition efficiency of ZIAMH nanomedicines was three fold higher than that of free drugs. Therefore, this study provides a new strategy for glucose metabolism-mediated bioenergetic therapy and PTT/CDT/CT combined therapy for tumors.Graphical

Engineered biomimetic cisplatin-polyphenol nanocomplex for chemo-immunotherapy of glioblastoma by inducing pyroptosis

Glioblastoma multiforme (GBM) is characterized by pronounced immune escape and resistance to chemotherapy-induced apoptosis. Preliminary investigations revealed a marked overexpression of gasdermin E (GSDME) in GBM. Notably, cisplatin (CDDP) demonstrated a capacity of inducing pyroptosis by activating caspase-3 to cleave GSDME, coupled with the release of proinflammatory factors, indicating the potential as a viable approach of inducing anti-tumor immune activation. For the effective delivery of CDDP, the CDDP-polyphenol nanocomplexes were prepared, and catalase and copper ions were incorporated to fortify structural integrity, enhance glutathione (GSH) responsiveness, and ameliorate tumor hypoxia. Additionally, BV2 microglial cells were engineered to overexpress programmed death-1 (PD-1), and the membrane is employed for nanocomplex coating, effectively blocking the CDDP-induced upregulation of programmed death ligand 1 (PD-L1). Furthermore, the angiopep-2 peptide was modified to efficiently cross the blood brain barrier and specifically target GBM cells. In vitro analyses confirmed potent cytotoxicity and characteristic induction of pyroptosis. In vivo assays corroborated the enhancement of tumor targeting, culminating in an obvious suppression of tumor proliferation. A notable activation of immune cells was observed within tumors and lymph nodes, indicative of a synergistic effect of chemotherapy and immunotherapy, underscoring its potential as a safe and efficacious therapeutic strategy against GBM.

Zinc nanoparticles from oral supplements accumulate in renal tumours and stimulate antitumour immune responses.

A successful therapeutic outcome in the treatment of solid tumours requires efficient intratumoural drug accumulation and retention. Here we demonstrate that zinc gluconate in oral supplements assembles with plasma proteins to form ZnO nanoparticles that selectively accumulate into papillary Caki-2 renal tumours and promote the recruitment of dendritic cells and cytotoxic CD8+ T cells to tumour tissues. Renal tumour targeting is mediated by the preferential binding of zinc ions to metallothionein-1X proteins, which are constitutively overexpressed in Caki-2 renal tumour cells. This binding event further upregulates intracellular metallothionein-1X expression to induce additional nanoparticle binding and retention. In both tumour animal models and human renal tumour samples, we show that ZnO nanoparticles actively cross the vascular wall to achieve high intratumoural accumulation. We further explore this feature of ZnO nanoparticles for the delivery of chemotherapeutics to mouse and rabbit cancer models. Our findings demonstrate that ZnO nanoparticles derived from supplements can serve as a multifunctional drug delivery and cancer immunotherapy platform.