Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.

Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.

Advances of E3 ligases in lung cancer.

Lung cancer is a leading cause of cancer-related death, and the most common type of lung cancer is non-small cell lung cancer, which accounts for approximately 85 % of lung cancer diagnoses. Recent studies have revealed that ubiquitination acts as a crucial part of the development and progression of lung cancer. The E1-E2-E3 three-enzyme cascade has a core function in ubiquitination, so targeted adjustments of E3 ligases could be used in lung cancer treatment. Hence, we elucidate research advances in lung cancer-related E3 ligases by briefly describing the structure and categorization of E3 ligases. Here, we provide a detailed review of the mechanisms by which lung cancer-related E3 ligases modify substrate proteins and regulate signaling pathways to facilitate or suppress cancer progression. We hope to show a new perspective on targeted precision therapy for lung cancer.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models.

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Mito-Specific Nutri-Hijacker Synergizing Mitochondrial Metabolism and Glycolysis Intervention for Enhanced Antitumor Bioenergetic Therapy.

Metabolic rewiring, a dynamic metabolic phenotype switch, confers that tumors exist and proliferate after fitness (or preadaptation) in harsh environmental conditions. Glycolysis deprivation was considered to be a tumor's metabolic Achilles heel. However, metabolic configuration can flexibly retune the mitochondrial metabolic ability when glycolysis is scared, potentially resulting in more aggressive clones. To address the challenge of mitochondrial reprogramming, an antiglycolytic nanoparticle (GRPP NP) containing a novel mitochondrial-targeted reactive oxygen species (ROS) generator (diIR780) was prepared to hijack glucose and regulate mitochondria, thus completely eliminating tumorigenic energy sources. In this process, GRPP NPs@diIR780 can catalyze endogenous glucose, leading to significantly suppressed glycolysis. Moreover, diIR780 can be released and selectively accumulated around mitochondria to generate toxic ROS. These combined effects, in turn, can hamper mitochondrial metabolism pathways, which are crucial for driving tumor progression. This synchronous intervention strategy enables utter devastation of metabolic rewiring, providing a promising regiment to eradicate tumor lesions without recurrence.

Stepwise Incremental Dose Schedule of Sirolimus Is Successfully Tolerated by a Patient With Lymphangioleiomyomatosis Who Was Initially Allergic to mTOR Inhibitors.

Lymphangioleiomyomatosis (LAM) is a rare disease involving the proliferation of LAM cells in the lungs and the axial lymphatic system and mechanistic target of rapamycin (mTOR) inhibitors are the only effective medicines for treating it. Patients suffering from LAM, who are allergic to mTOR inhibitors can be treated by desensitizing them to the medicine. A 39-year-old woman presented with dyspnea caused by chylous pleural effusion, ascites, and retroperitoneal lymphangioleiomyomas. She was diagnosed with LAM based on the presence of LAM cell clusters (LCCs) in chylous pleural effusion and elevated serum vascular endothelial growth factor D (VEGF-D) concentration. She was allergic to cedars and yellowtails. Although she was started on sirolimus for treating LAM, the drug had to be discontinued on day 45 because of the appearance of a skin rash on her trunk. A year later, another oral mTOR inhibitor, everolimus, was initiated but had to be discontinued because of the appearance of cutaneous reactions. Since mTOR inhibitors are the only effective molecular-target medicines for LAM, desensitization to sirolimus was attempted by initiating exposure to sirolimus at a low dose followed by stepwise dose escalation. Eventually, the patient tolerated a dose of 0.5 mg/day of sirolimus, which resulted in a trough concentration of approximately 2 ng/ml in blood, without adverse cutaneous reactions; furthermore, clinically relevant effects were observed as her LAM condition reduced and stabilized. This case study illustrates that mTOR inhibitor therapy for LAM should not be abandoned because of allergic cutaneous reactions. Physicians must find a dose that balances adverse events and therapeutic effects to ensure continued treatment for patients with LAM. Furthermore, the possible mechanisms for mTOR inhibitor-induced cutaneous reactions have been discussed.

Chemokines and lymphocyte homing in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4ß7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-ß, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-ß receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

Myeloid-derived suppressor cells in cancer: therapeutic targets to overcome tumor immune evasion.

Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.

Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2α.

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.

Synergistic Effects of Chemotherapy and Phototherapy on Ovarian Cancer Using Follicle-Stimulating Hormone Receptor-Mediated Liposomes Co-Loaded with SN38 and IR820.

We have developed an ovarian cancer-targeted drug delivery system based on a follicle-stimulating hormone receptor (FSHR) peptide. The lipophilic chemotherapeutic drug SN38 and the photosensitizer IR820 were loaded into the phospholipid bilayer of liposomes. The combination of chemotherapy and phototherapy has become a promising strategy to improve the therapeutic effect of chemotherapy drugs on solid tumors. IR820 can be used for photodynamic therapy (PDT), effectively converting near-infrared light (NIR) into heat and producing reactive oxygen species (ROS), causing damage to intracellular components and leading to cell death. In addition, PDT generates heat in near-infrared, thereby enhancing the sensitivity of tumors to chemotherapy drugs. FSH liposomes loaded with SN38 and IR820 (SN38/IR820-Lipo@FSH) were prepared using thin-film hydration-sonication. FSH peptide binding was analyzed using 1H NMR spectrum and Maldi-Tof. The average size and zeta potential of SN38/IR820-Lipo@FSH were 105.1 ± 1.15 nm (PDI: 0.204 ± 0.03) and -27.8 ± 0.42 mV, respectively. The encapsulation efficiency of SN38 and IR820 in SN38/IR820-Lipo@FSH liposomes were 90.2% and 91.5%, respectively, and their release was slow in vitro. FSH significantly increased the uptake of liposomes, inhibited cell proliferation, and induced apoptosis in A2780 cells. Moreover, SN38/IR820-Lipo@FSH exhibited better tumor-targeting ability and anti-ovarian cancer activity in vivo when compared with non-targeted SN38/IR820-Lipo. The combination of chemotherapy and photodynamic treatment based on an FSH peptide-targeted delivery system may be an effective approach to treating ovarian cancer.

The application strategy of liposomes in organ targeting therapy.

Liposomes-microscopic phospholipid bubbles with bilayered membrane structure-have been a focal point in drug delivery research for the past 30 years. Current liposomes possess a blend of biocompatibility, drug loading efficiency, prolonged circulation and targeted delivery. Tailored liposomes, varying in size, charge, lipid composition, and ratio, have been developed to address diseases in specific organs, thereby enhancing drug circulation, accumulation at lesion sites, intracellular delivery, and treatment efficacy for various organ-specific diseases. For further successful development of this field, this review summarized liposomal strategies for targeting different organs in series of major human diseases, including widely studied cardiovascular diseases, liver and spleen immune diseases, chronic or acute kidney injury, neurodegenerative diseases, and organ-specific tumors. It highlights recent advances of liposome-mediated therapeutic agent delivery for disease intervention and organ rehabilitation, offering practical guidelines for designing organ-targeted liposomes. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures.

AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model.

Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood-brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.

Long-Term Outcome After Discontinuation of CGRP-Targeting Therapy for Migraine.

PURPOSE OF REVIEW: Calcitonin gene-related peptide (CGRP)-targeting agents are potential candidates for disease-modifying migraine drugs. However, most studies on CGRP-targeting agents have assessed efficacy outcomes rather than long-term effects after discontinuation. This review aimed to synthesize and scrutinize the latest clinical data on the outcomes after the discontinuation of CGRP-targeting therapy in patients with episodic and chronic migraine, with a particular focus on chronic migraine. RECENT FINDINGS: Real-world studies involving patients with migraine have reported consistent findings of worsened headache frequency and quality of life after the discontinuation of CGRP monoclonal antibodies (CGRP mAbs). Although many patients maintain improvements for up to 4 months after discontinuation compared to baseline (before starting CGRP mAbs), no studies have evaluated the effects of stopping treatment for > 5 months, which is the five-half-life of CGRP mAbs. Several studies have suggested that patients treated with CGRP receptor mAbs experience more rapid deterioration than those treated with CGRP ligand mAbs after discontinuing CGRP mAbs. The results of real-world studies suggest that for many patients with migraine, the benefits of CGRP mAbs diminish months after discontinuation. Therefore, anti-CGRP therapies may not be considered disease-modifying. However, the comprehensive assessment of the disease-modifying potential of these drugs requires studies with extended treatment and cessation durations.

Intra-Articular Injection of PLGA/Polydopamine Core-Shell Nanoparticle Attenuates Osteoarthritis Progression.

Osteoarthritis (OA) is a common joint disease characterized by progressive cartilage degeneration. Unfortunately, currently available clinical drugs are mainly analgesics and cannot alleviate the development of OA. Kartogenin (KGN) has been found to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes for the treatment of cartilage damage in early OA. However, KGN, as a small hydrophobic molecule, is rapidly cleared from the synovial fluid after intra-articular injection. This study synthesized a KGN-loaded nanocarrier based on PLGA/polydopamine core/shell structure to treat OA. The fluorescence signal of KGN@PLGA/PDA-PEG-E7 nanoparticles lasted for 4 weeks, ensuring long-term sustained release of KGN from a single intra-articular injection. In addition, the polyphenolic structure of PDA enables it to effectively scavenge reactive oxygen species, and the BMSC-targeting peptide E7 (EPLQLKM) endows KGN@PLGA/PDA-PEG-E7 NPs with an effective affinity for BMSCs. As a result, the KGN@PLGA/PDA-PEG-E7 nanoparticles could effectively induce cartilage in vitro and protect the cartilage and subchondral bone in a rat ACLT model. This therapeutic strategy could also be extended to the delivery of other drugs, targeting other tissues to treat joint diseases.

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor.

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Targeting neutrophils: Mechanism and advances in cancer therapy.

BACKGROUND: Cancer is a thorny problem which cannot be conquered by mankind at present and recent researchers have put their focus on tumor microenviroment. Neutrophils, the prominent leukocytes in peripheral blood that accumulate in tumours, serves as frontline cells in response to tumour progression owing to the rapid development of micro biotechnology. Hence, targeted therapy with these neutrophils has made targeting treatment a promising field in cancer therapy. MAIN BODY: We broadly summarise some studies on the phenotypes and functions of tumour-associated neutrophils as well as the unique web-like products of neutrophils that play a role in cancer progression-neutrophil extracellular traps-and the interactions between neutrophils and the tumour microenvironment. Moreover, several targeted neutrophils therapeutic studies have made some progress and provided potential strategies for the treatment of cancer. CONCLUSION: This review aims to offer a holistic perspective on therapeutic interventions targeting neutrophils to further inspire more researches on cancer therapies.

A multiscale modeling study of nanoparticle-based targeting therapy against atherosclerosis.

Although researches on nanoparticle-based (NP-based) drug delivery system for atherosclerosis treatment have grown rapidly in recent years, there are limited studies in quantifying the effects of targeting drugs on plaque components and microenvironment. The purpose of the present study was to quantitatively assess the targeting therapeutic effects against atherosclerosis by establishing a multiscale mathematical model. The multiscale model involved subcellular, cellular and microenvironmental scales to simulate lipid catabolism, macrophage behaviors and dynamics of microenvironmental components, respectively. In vitro and in vivo experimental data were integrated into the mathematical model according to Bayesian statistics, in order to evaluate the therapeutic effects of a proposed NP-based platform for macrophage-specific delivery to simultaneously deliver SR-A siRNA (to reduce LDL uptake) and LXR-L (to stimulate cholesterol efflux). Dosage variation analysis was then performed to investigate the drug efficacy under varied dosage combinations of SR-A siRNA and LXR-L. The simulation results demonstrated that the dynamics of the microenvironmental components presented different developments in Untreated and Treated groups. We also found that the balance of lipid metabolism between uptake and efflux resulted in the improvement of lipid and inflammatory microenvironment, consequently in the plaque regression. In addition, the model predicted optimized dosage combinations according to the co-effect analysis of the two drugs on the lipid microenvironment. This study suggests that multiscale modeling can be a powerful quantitative tool for estimating the therapeutic effects of targeting drugs for plaque regression and designing the enhanced treatment strategies against atherosclerosis.

Nanozymes-Mediated Cascade Reaction System for Tumor-Specific Diagnosis and Targeted Therapy.

Cascade reactions are described as efficient and versatile tools, and organized catalytic cascades can significantly improve the efficiency of chemical interworking between nanozymes. They have attracted great interest in many fields such as chromogenic detection, biosensing, tumor diagnosis, and therapy. However, how to selectively kill tumor cells by enzymatic reactions without harming normal cells, as well as exploring two or more enzyme-engineered nanoreactors for cascading catalytic reactions, remain great challenges in the field of targeted and specific cancer diagnostics and therapy. The latest research advances in nanozyme-catalyzed cascade processes for cancer diagnosis and therapy are described in this article. Here, various sensing strategies are summarized, for tumor-specific diagnostics. Targeting mechanisms for tumor treatment using cascade nanozymes are classified and analyzed, "elements" and "dimensions" of cascade nanozymes, types, designs of structure, and assembly modes of highly active and specific cascade nanozymes, as well as a variety of new strategies of tumor targeting based on the cascade reaction of nanozymes. Finally, the integrated application of the cascade nanozymes systems in tumor-targeted and specific diagnostic therapy is summarized, which will lay the foundation for the design of more rational, efficient, and specific tumor diagnostic and therapeutic modalities in the future.

Genetically engineered macrophages as living cell drug carriers for targeted cancer therapy.

Precise targeting is a major prerequisite for effective cancer therapy because it ensures a sufficient therapeutic dosage in tumors while minimizing off-target side effects. Herein, we report a live-macrophage-based therapeutic system for high-efficiency tumor therapy. As a proof of concept, anti-human epidermal growth factor receptor-2 (HER2) affibodies were genetically engineered onto the extracellular membrane of macrophages (AE-Mφ), which further internalized doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) nanoparticles (NPs) to produce a macrophage-based therapeutic system armed with anti-HER2 affibodies. NPs(DOX)@AE-Mφ were able to target HER2+ cancer cells and specifically elicit affibody-mediated cell therapy. Most importantly, the superior HER2 + -targeting capability of NPs(DOX)@AE-Mφ greatly guaranteed high accumulation at the tumor site for improved chemotherapy, which acted synergistically with cell therapy to significantly enhance anti-tumor efficacy. This study suggests that NPs(DOX)@AE-Mφ could be utilized as an innovative 'living targeted drug' platform for combining both macrophage-mediated cell therapy and targeted chemotherapy for the individualized treatment of solid tumors.

How donanemab data address the coverage with evidence development questions.

The Centers for Medicare & Medicaid Services (CMS) established a class-based National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for Alzheimer's disease (AD) with patient access through Coverage with Evidence Development (CED) based on three questions. This review, focused on donanemab, answers each of these CED questions with quality evidence. TRAILBLAZER-ALZ registration trials are presented with supporting literature and real-world data to answer CED questions for donanemab. TRAILBLAZER-ALZ registration trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive early symptomatic AD participants, and lowered their risk of disease progression while key safety risks occurred primarily within the first 6 months and then declined. Donanemab meaningfully improved health outcomes with a manageable safety profile in an early symptomatic AD population, representative of Medicare populations across diverse practice settings. The donanemab data provide the necessary level of evidence for CMS to open a reconsideration of their NCD. HIGHLIGHTS: Donanemab meaningfully improved outcomes in trial participants with early symptomatic Alzheimer's disease. Comorbidities in trial participants were consistent with the Medicare population. Co-medications in trial participants were consistent with the Medicare population. Risks associated with treatment tended to occur in the first 6 months. Risks of amyloid-related imaging abnormalities were managed with careful observation and magnetic resonance imaging monitoring.