Ultrasound-mediated immunotherapy has emerged as a promising non-invasive approach for cancer treatment due to its deep tissue penetration and precise spatiotemporal control. Ultrasound induces immunogenic cell death through mechanical, cavitation, and sonodynamic effects, triggering the release of tumor antigens and danger-associated molecular patterns that activate both innate and adaptive immune responses. However, ultrasound therapy alone demonstrates limited immune-activating capacity. Recent advances in nanomedicine, particularly through sonosensitizers and piezoelectric ultrasound-responsive nanoplatforms, have significantly enhanced this approach by amplifying reactive oxygen species production, enabling targeted drug delivery, and remodeling the tumor immune microenvironment. The field is progressively advancing from localized tumor destruction toward systemic immune activation, particularly through combination with immunotherapy strategies targeting PD-1, PD-L1, and CTLA-4. While checkpoint inhibitors and CAR-T cell therapies have revolutionized cancer treatment for hematologic malignancies, solid tumors remain challenging due to their complex biology and immunosuppressive characteristics. Ultrasound immunotherapy, enhanced by nanomedicine innovations, addresses these limitations and offers new opportunities for precision immunotherapy in solid tumors, though clinical translation challenges remain.

Melanoma presents significant clinical challenges due to its heterogeneity, early metastatic potential, and development of treatment resistance. While conventional tissue biopsy and imaging remain diagnostic cornerstones, they suffer from invasiveness, sampling bias, and inability to monitor disease evolution longitudinally. This review examines small extracellular vesicles and exosomes—endogenous bio-nanomaterials circulating stably in body fluids—as promising alternatives for minimally invasive liquid biopsy and real-time disease monitoring. Exosomes carry multi-omic cargo including DNA, RNA, proteins, and lipids that reflect tumor-immune dynamics. Beyond diagnostic applications, engineered exosomal nanomaterials can be functionalized and loaded with therapeutic payloads to enhance targeted delivery and support combination immunotherapy regimens. The review synthesizes mechanistic roles of exosomes in melanoma progression and highlights key liquid-biopsy biomarkers such as exosomal PD-L1 and EV-miRNA/protein signatures. However, significant translational barriers remain, including standardization, scalable manufacturing, safety assessment, and robust clinical validation required to integrate these technologies into clinical practice for improved patient stratification and disease monitoring.

# Summary This open-access review article, published in July 2026, examines next-generation nanocarriers designed to deliver synergistic chemoimmunotherapy while engineering the tumor microenvironment for enhanced precision cancer treatment. The article synthesizes current research on how advanced nanoparticle-based delivery systems can simultaneously administer chemotherapy and immunotherapy agents, overcoming traditional limitations of conventional treatments. By targeting and modulating the immunosuppressive tumor microenvironment, these nanocarriers enable improved drug accumulation at tumor sites while reducing systemic toxicity. The approach represents a significant advancement in personalized oncology, combining nanotechnology with immunological principles to achieve superior therapeutic outcomes. This research matters because it addresses critical challenges in cancer treatment, including poor drug bioavailability, off-target effects, and immune evasion. The integration of chemotherapy and immunotherapy through engineered nanocarriers offers promising potential to improve patient response rates and survival outcomes across multiple cancer types, positioning this technology as a cornerstone of future precision medicine strategies in oncology.

Exosomes, naturally occurring extracellular vesicles, are emerging as promising biological carriers for cancer therapy, offering inherent biocompatibility and the ability to overcome biological barriers that limit traditional treatments. According to GLOBOCAN 2022 data highlighting 19.3 million new cancer cases globally, there is urgent need for more effective therapeutic approaches. This review published in the International Journal of Nanomedicine by researchers at Jilin University examines engineered exosomes, hybrid exosomes, and exosome mimics as delivery platforms for multiple cancer treatment modalities including chemotherapy, gene therapy, immunotherapy, and theranostics. While native exosomes face limitations such as low production yields, heterogeneity, and poor drug-loading efficiency, engineered variants and biomimetic platforms can preserve biological functionality while improving scalability and reproducibility. However, significant obstacles remain for clinical translation, including manufacturing standardization, cargo reproducibility, safety evaluation, and regulatory approval. This translational perspective addresses critical engineering aspects essential for transitioning exosome-inspired nanocarriers from laboratory development to clinical application in cancer treatment.

This review examines nanosystem-mediated phototherapy approaches combining photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) to overcome tumor treatment limitations. CDT generates hydroxyl radicals through Fenton reactions but faces constraints from the tumor microenvironment, including insufficient hydrogen peroxide, suboptimal pH, robust glutathione-mediated reactive oxygen species scavenging, and hypoxia. PDT and PTT serve as synergistic modalities that enhance oxidative stress and accelerate Fenton reaction kinetics, respectively. Rather than merely cataloguing nanomaterials, this analysis constructs a mechanistic framework detailing how PDT and PTT complement CDT through reaction kinetics modulation, substrate replenishment, and antioxidant defense inhibition. The review systematically covers synergistic principles including ROS cascade amplification, glutathione depletion-initiated ferroptosis, tumor microenvironment acidification, extracellular matrix degradation, and immunogenic cell death. It summarizes advances in dual and triple-modal nanoplatforms, highlighting evolution from basic thermochemical designs to sophisticated architectures featuring tumor microenvironment-responsive delivery, second near-infrared deep-tissue penetration, enzyme-cascaded self-substrate supply, and theranostic integration, while addressing clinical translation challenges.

Fibrosis, as a shared hallmark, is prevalent in a variety of chronic diseases. However, current pharmacological strategies for fibrosis are limited in clinical application and efficacy due to issues such as insufficient targeting capability, systemic toxicity, and low bioavailability. The advent of nanotechnology has ushered in an era of novel therapeutic strategies for fibrosis, revolutionizing the treatment landscape. This article systematically reviews the dual applications of nanomaterials in fibrosis treatment: first, as nanoparticle drug delivery systems (NDDS) to enhance targeting, control release, and improve drug bioavailability; second, as therapeutic agents directly alleviating the onset and progression of fibrosis. Furthermore, this article further discusses the applications of nanomaterials with diverse designs and compositions in fibrosis affecting different organs.

T cell engagers (TCEs) represent a promising immunotherapy approach, with eight molecules currently FDA-approved for hematologic malignancies and two for solid tumors. These bispecific agents redirect endogenous T cells to attack cancer cells by simultaneously engaging tumor-associated antigens and CD3 on T cells. However, TCE efficacy in solid tumors remains limited, necessitating next-generation strategies to maintain T cell fitness within the hostile tumor microenvironment. This mini-review from Amgen researchers proposes that cellular metabolism is a critical but underexplored regulator of TCE responses. The authors examine how three major T cell signaling axes—the T cell receptor complex, costimulatory receptors, and cytokine receptors—drive metabolic reprogramming that enables immune function and influences T cell fate. The paper further explores how environmental factors such as nutrient availability and metabolic stressors within the tumor microenvironment impair TCE efficacy. By integrating understanding of immunological signaling, cellular metabolism, and immune programming, researchers can design more effective next-generation TCEs capable of overcoming metabolic barriers to anti-tumor immunity in solid tumors.

Researchers have developed a novel immunotherapy approach that reprograms macrophages to combat cancer by decorating cancer cell membranes with bacteria-derived pathogen-associated molecular patterns (PAMPs) formulated into nanoparticles. These PAMP nanoparticles trigger macrophages to shift from an immunosuppressive to an inflammatory phenotype, significantly increasing phagocytosis of cancer cells and stimulating production of inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. Transcriptomic analysis revealed that macrophages responding to PAMP-decorated cancer cells activate signaling pathways similar to their response against bacteria. In mouse tumor models, locally injected PAMP nanoparticles suppressed tumor growth, with enhanced therapeutic efficacy when combined with the chemotherapeutic drug doxorubicin. Both PAMP nanoparticle monotherapy and the combination approach demonstrated significantly increased median survival with complete remission cases compared to doxorubicin alone. This research offers promising insights into leveraging macrophages as an effective cell-based cancer immunotherapy platform, potentially addressing limitations of existing adoptive cell therapies in treating solid tumors.

Researchers have developed a novel therapeutic approach combining bone marrow mesenchymal stem cell-derived exosome-liposome hybrid nanoparticles that simultaneously target CSF1R and PD-L1 pathways to enhance tumor-associated macrophage phagocytosis. This study, published in Cancer Nanotechnology in July 2026, demonstrates that the dual-targeting strategy effectively reprograms the immunosuppressive tumor microenvironment by inhibiting colony-stimulating factor 1 receptor signaling while blocking programmed death ligand 1 checkpoint interactions. The hybrid delivery system leverages the biocompatibility and immunomodulatory properties of BM-MSC-derived exosomes combined with liposomal formulation to improve drug efficacy and cellular uptake. In vitro experiments revealed that this combinational approach significantly augments macrophage-mediated tumor cell phagocytosis in a microenvironment-dependent manner, suggesting context-specific therapeutic responses. This research highlights the potential of engineered nanoparticle systems to overcome tumor immunosuppression through multi-target engagement, offering promising implications for developing more effective immunotherapeutic strategies against cancer while potentially reducing systemic toxicity through targeted nano-delivery mechanisms.

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication by transferring proteins, nucleic acids, and lipids. This review explores recent advances in engineering EVs as programmable immune interfaces for therapeutic applications. Rather than serving merely as delivery vehicles, engineered EVs integrate antigen specificity, target-cell recognition, therapeutic cargo, and immunostimulatory or tolerogenic signals within a single nanoscale particle. The article examines modular engineering strategies including surface display, cellular targeting, and cargo loading approaches, with applications spanning cancer immunotherapy, immune suppression, and antigen-specific tolerance induction. Key platforms discussed include antigen-presenting EVs, cytotoxic and RNA-loaded EVs, checkpoint-modulatory EVs, and mesenchymal stem cell-derived EVs for autoimmune and inflammatory diseases. The review emphasizes clinical translation challenges encompassing manufacturing, characterization, potency assays, biodistribution, safety, and regulatory requirements. The authors conclude that programmable EV immune interfaces represent a versatile foundation for next-generation cancer immunotherapy and context-dependent immune regulation, offering significant therapeutic potential for diverse clinical indications.

Researchers have developed a novel positron emission tomography (PET) imaging system to monitor gene expression in the brain, addressing a significant gap in neurological research tools. The team engineered a fluorine-18-labeled HaloTag ligand designed to penetrate the blood-brain barrier and form covalent bonds with HaloTag protein expressed in target cells. This exogenous reporter system overcomes limitations of existing approaches that rely on endogenous brain receptors with unpredictable expression in disease states. The tracer demonstrated specific binding in human cells expressing HaloTag and successfully enabled non-invasive imaging of viral gene transfer to striatal neurons in mice, with clear detection of reporter-expressing tissue and rapid clearance from surrounding regions. Optical imaging confirmed viral distribution, and a transgenic model expressing HaloTag fused to a postsynaptic protein validated detection of physiologically expressed intraneuronal targets. This modular platform establishes a valuable tool for preclinical neurological disease modeling and quantifying gene expression in living brains, with potential applications for monitoring gene therapy efficacy in clinical settings—a capability previously unavailable for neurological applications despite widespread use in oncology.

Photodynamic therapy (PDT) represents a promising cancer treatment approach that operates through mechanisms beyond traditional apoptotic pathways. This comprehensive review, published in the Journal of Biomedical Science in July 2026, examines how PDT induces multiple non-apoptotic cell death mechanisms to combat tumors. The research synthesizes current understanding of PDT's antitumor effects, demonstrating that the therapy activates diverse cellular death pathways including autophagy, necrosis, and immunogenic cell death, rather than relying solely on apoptosis. This multi-modal approach is significant because it potentially overcomes resistance mechanisms that tumors develop against conventional therapies targeting single death pathways. By leveraging photosensitizing agents activated by light exposure, PDT generates reactive oxygen species that trigger these varied death mechanisms simultaneously. The findings suggest PDT's enhanced clinical efficacy and reduced likelihood of therapeutic resistance development. This open-access review provides valuable insights for oncologists and biomedical researchers exploring combination therapies and advancing PDT as a viable treatment modality for various cancer types.

Exosomes represent a promising advancement in cancer therapeutics, addressing significant limitations of traditional treatments that suffer from poor tumor targeting, toxicity, and inability to penetrate biological barriers. This comprehensive review in the International Journal of Nanomedicine examines how engineered exosomes, hybrid exosomes, and exosome mimics can deliver multiple therapeutic modalities including chemotherapy, gene therapy, immunotherapy, and theranostic applications. The biomimetic and hybrid platforms overcome critical challenges inherent to native exosomes, such as low production yields, drug-loading inefficiency, and scalability issues, while maintaining essential biological functions. The authors emphasize that despite the therapeutic potential, standardization in manufacturing, reproducibility of cargo loading, comprehensive safety evaluation, and regulatory approval remain significant hurdles to clinical translation. Given that GLOBOCAN 2022 reported 19.3 million new cancer cases and 10 million cancer-related deaths worldwide, the development of these advanced nanocarrier systems is urgently needed to improve treatment outcomes and patient survival rates globally.

Extracellular vesicles, including exosomes, exomeres and supermeres, represent a diverse family of nanoparticles that mediate intercellular communication and carry functional cargo between cells. This comprehensive research library examines how donor cell type, metabolic state and physiological conditions shape vesicle formation and selective cargo loading of proteins, RNA and DNA. The collection establishes experimental approaches to confirm causal signalling roles and explores the cell biology underlying vesicle targeting, internalization and intracellular cargo delivery. High-resolution fractionation techniques distinguish genuine exosomal constituents from co-isolated material, clarifying vesicle composition and function. The library addresses international reporting standards and methodological guidelines essential for rigorous extracellular vesicle research. Particular emphasis falls on mesenchymal stem cell-derived vesicles, which demonstrate significant regenerative potential through microRNA cargo and DNA clearance mechanisms. The field has evolved from foundational studies of vesicle biology to recognition of exosomes as adaptable therapeutic delivery systems. Understanding how intrinsic and environmental factors determine extracellular vesicle signalling is critical for developing tissue-targeted, vesicle-based treatments that maximize therapeutic efficacy.

Nucleic acid therapeutics, including oligonucleotides, messenger RNA, and DNA, represent promising drug modalities for treating various diseases, yet their efficient delivery remains a significant challenge. Dendrimers—highly branched, structurally precise nanostructures—offer a versatile platform for targeted nucleic acid delivery. Their unique architecture enables tunable physicochemical properties, high cargo loading, efficient cellular uptake, and endosomal escape capabilities. Current engineering strategies focus on rational design of cationic or ionizable features, structural flexibility, amphiphilicity, and surface functionalization to enhance protection and enable organ-specific or cell-specific targeting. Dendrimers have successfully delivered diverse nucleic acid types, including small interfering RNA, microRNA, antisense oligonucleotides, small activating RNA, DNA, and messenger RNA, supporting applications in gene silencing, activation, editing, and addition. However, clinical translation faces significant obstacles including complex manufacturing processes, long-term safety concerns, and regulatory complexities. Future advancement requires simplified synthetic processes, enhanced tissue-specific targeting capabilities, and solutions to manufacturing scalability challenges to fully realize dendrimers' therapeutic potential.

Researchers at Jiangnan University developed biomimetic CuZnS@BSA nanoclusters to address triple-negative breast cancer (TNBC) resistance mechanisms. The nanoregulators exploit pH-triggered sequential release of hydrogen sulfide, copper ions, and zinc ions within the acidic tumor microenvironment. In vitro studies using 4T1 cells demonstrated that hydrogen sulfide depletes glutathione antioxidant defenses, while copper ions induce cuproptosis—a copper-dependent cell death pathway that circumvents apoptosis resistance typical in TNBC. Zinc ions promote recognition of mitochondrial DNA, activating the cGAS-STING signaling pathway. In vivo experiments using subcutaneous and lung metastasis mouse models showed the platform significantly increased CD8+ T cell infiltration and dendritic cell maturation, effectively remodeling the tumor microenvironment from an immunologically "cold" to "hot" state. When combined with PD-L1 checkpoint blockade, the treatment demonstrated potent suppression of both primary tumor growth and metastatic disease. This approach elegantly bridges metabolic reprogramming with systemic immune activation, offering a promising therapeutic strategy for TNBC patients with traditional apoptosis-resistant tumors.

Cell therapy has emerged as a transformative approach to oncology, driven by the rising global cancer burden projected to reach over 35 million new cases annually by 2050. Beyond the initial success of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, the field now encompasses diverse strategies including TCR-engineered T cells, tumor-infiltrating lymphocytes, gamma delta T cells, CAR-natural killer cells, CAR-macrophages, and dendritic cell-based approaches. A significant paradigm shift is underway, transitioning from autologous therapies to allogeneic "off-the-shelf" platforms, with CAR-NK and CAR-NKT cells showing particular promise due to their low immunogenicity and reduced graft-versus-host disease risk. Emerging in vivo engineering technologies that deliver CAR genes directly at tumor sites offer potential cost and manufacturing advantages. Despite substantial progress, major obstacles persist, including tumor heterogeneity, immunosuppressive microenvironments, and treatment-related toxicity. Future advancement will integrate multiomics analysis, artificial intelligence, and synthetic biology to enhance safety, efficacy, and accessibility of cell therapies across diverse cancer types.

Efficient delivery of CRISPR/Cas genome editing tools to primary cells remains a significant barrier to clinical translation of this promising therapeutic technology. Researchers at the Center for Genome Research, Institute of Gene Biology Russian Academy of Sciences developed a detailed protocol for producing virus-like particles (VLPs) incorporating the AsCas12a nuclease as an alternative to traditional SpCas9-based systems. The team optimized both small-scale and large-scale production methods using three transfection approaches—cationic lipids, polyethyleneimine, and calcium-phosphate—demonstrating that calcium-phosphate transfection proved effective for scalable manufacturing. The NanoMEDIC VLP platform carrying AsCas12a with CMV-driven guide RNA achieved up to 60% CXCR4 knockout efficiency in Jurkat T cells, substantially outperforming conventional SpCas9-VLP systems. VLPs derived from HIV-1 and murine leukemia virus provide distinct advantages as delivery vehicles: they efficiently transduce diverse cell types, lack viral genomes to minimize integration risks, and enable transient nuclease expression that reduces off-target effects. This advancement addresses a critical clinical bottleneck by establishing scalable production protocols for enhanced CRISPR delivery systems, accelerating the therapeutic translation of genome editing technologies.

Exosomes, small lipid bilayer-enclosed particles measuring 30 to 150 nanometers, have emerged as promising therapeutic drug delivery vehicles. Derived from the endosomal system and released by virtually all cell types, exosomes function as sophisticated intercellular communicators capable of transferring proteins, lipids, RNA, microRNA, and DNA fragments between cells. Their therapeutic potential stems from intrinsic advantages including natural protection of cargo from enzymatic degradation and immune clearance, inherent cell and tissue tropism via surface proteins, small size enabling penetration of biological barriers including the blood-brain barrier, and comparatively low immunogenicity compared to synthetic carriers like liposomes and polymeric nanoparticles. This natural origin represents a significant shift in nanomedicine away from purely synthetic platforms toward biologically derived alternatives. Unlike synthetic nanocarriers that accumulate in liver and spleen, exosomes derived from autologous sources can better evade immune recognition and potentially improve therapeutic targeting. However, translational challenges remain, including cargo heterogeneity, batch variability, and underdeveloped engineering tools for converting naturally heterogeneous biological products into reproducible pharmaceuticals. The field is rapidly expanding applications to chemotherapeutics, nucleic acid therapeutics, and other biologics.

Stimuli-responsive materials enable temporal and spatial control over drug delivery and action. Traditional triggerable therapeutics are largely based on small molecules, like prodrugs and photodynamic therapy agents. Advances in nanotechnology and micromaterials have greatly expanded the field, as evidenced by clinically translated hyperthermia-generating iron oxide nanoparticles, radiotherapy-enhancing hafnium oxide nanoparticles, and ultrasound-responsive microbubbles.