Ming Ma

Immunotherapy has emerged as a pivotal strategy in cancer treatment. However, tumor metabolic reprogramming not only promotes cancer cell survival but also fosters an immunosuppressive tumor microenvironment (TME), thereby hindering immune activation. To address these challenges, we developed a novel multifunctional hybrid nanoplatform, termed VTLM, via microfluidics‐assisted self‐assembly of bioactive vanadium species and an arginine‐based nitric oxide (NO) donor. This nanoplatform synergistically modulates tumor metabolism to potentiate antitumor immunity. Specifically, we observed that vanadium species in VTLM reduce pyruvate kinase M2 (PKM2) expression and enzymatic activity, which may contribute to the suppression of tumor glycolysis, while tumor cell‐targeted NO release induces mitochondrial damage, ultimately enforcing a dual metabolic blockade. This strategy overcomes the metabolic plasticity of tumor cells, a major obstacle in single‐pathway metabolic targeting. Importantly, VTLM‐induced metabolic collapse not only drives lactate depletion within the TME but also promotes immunogenic cell death, thereby reversing immunosuppression and amplifying antitumor responses. Furthermore, VTLM exhibited marked therapeutic efficacy in a 4T1 subcutaneous tumor model, achieving an 80.7% tumor weight‐based inhibition rate alongside robust intratumoral immune activation. Collectively, this study establishes a nanoplatform centered on multi‐metabolic regulation, which may hold potential for further preclinical evaluation as a strategy to enhance cancer immunotherapy.

As a bridge between innate sensing and adaptive immunity, the functional state of dendritic cells (DCs) is a critical determinant of protective immune responses. Inflammasome activation can induce a “hyperactive” state characterized by highly activated DCs with preserved viability, enhanced antigen presentation, migration capacity, and IL-1β secretion, representing an ideal condition for eliciting robust cytotoxic T lymphocyte (CTL) responses. However, attempts to apply this state in cancer vaccines face constraints including safety concerns, formulation complexity, and limited control over stimulation strength. Here, we develop a lipid nanoparticle (LNP) platform that combines plasmid DNA (pDNA) with fatty acids to optimize the inflammasome activity and direct DCs toward hyperactivation. Following the establishment and screening of the fatty acid-incorporated plasmid lipid nanoparticle (FA-pLNP) library, a palmitic acid formulation designated PA15 is identified as the lead candidate to induce DC hyperactivation. Mechanistic studies reveal that pDNA provides nuclear factor kappa B (NF-κB)-mediated priming, while palmitic acid promotes NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome assembly, enabling effective interleukin-1β (IL-1β) release and subsequent immune activation. Therapeutic vaccination with PA15 demonstrated significant antitumor efficacy in mouse tumor models. Collectively, this work provides a practical strategy for inducing hyperactive DCs and establishes a general design principle for next-generation cancer vaccines.

Background: Osteosarcoma (OS) is an aggressive bone tumor. The lack of physiologically relevant three-dimensional models that recapitulate the native tumor microenvironment hampers drug development and mechanistic studies. The study aimed to develop bone-mimetic microspheres for the construction of an OS model. Materials and Methods: We employed droplet microfluidics to fabricate bone-mimetic microspheres (named MSHA) from a composite of gelatin methacryloyl, polyethylene glycol diacrylate, and nano-hydroxyapatite (nHA). MNNG/HOS cells were cultured on MSHA microspheres and subsequently evaluated for their bioactivity and capabilities of stemness, migration, and invasion. Results: The microfluidic platform enabled efficient and scalable production of highly uniform MSHA microspheres with controlled sizes. MNNG/HOS cells cultured on MSHA maintained high viability and spontaneously formed compact tumor spheroids after 7 days. Compared with two-dimensional cultures, cells cultured on these microsphere-based platforms exhibited enhanced migration and invasion capacities, along with increased expression of relevant biomarkers. RNA sequencing further revealed the activation of cancer-related pathways. Notably, the incorporation of nHA into microspheres amplified these malignant phenotypes, potentially through the activation of ECM–receptor interaction and calcium signaling pathways. Conclusions: The microfluidics-fabricated MSHA microspheres, as biomimetic three-dimensional culture scaffolds, offer a promising platform for applications in mechanistic studies of osteosarcoma progression and drug screening.

Bone is a dynamic and multifunctional tissue that provides mechanical support, regulates mineral homeostasis, supports hematopoiesis, and relies on complex interactions among multiple cell types. The increasing incidence of bone-related diseases, such as osteoporosis, osteoarthritis, fracture non-union, and bone cancer, highlights the need for in vitro models that better reflect human bone physiology. Bone-on-a-chip technology, developed through advances in microfluidics, biomaterials, and tissue engineering, offers a promising approach to recreate key features of the bone microenvironment in vitro. By incorporating bone-mimicking materials, relevant bone cells, vascular components, fluid perfusion, and mechanical stimulation, these platforms allow more realistic investigation of bone remodeling, regeneration, disease mechanisms, and drug responses. In parallel, bone organoids and their integration with microfluidic chips have further expanded the capabilities of in vitro bone models by enabling the formation of self-organized, human-relevant bone tissues with increased cellular complexity. This review summarizes recent progress in bone-on-a-chip systems, including models for osteogenesis and bone regeneration, vascularized bone, bone marrow and hematopoietic niches, cancer bone metastasis, and mechanobiological studies. Key design principles, materials, cellular components, and applications in disease modeling, drug screening, toxicity assessment, and personalized medicine are discussed. Current challenges and future directions are also discussed to support the continued development of more physiologically relevant in vitro bone models.

Background: Liposome particles with smaller sizes could increase transdermal drug delivery efficacy for enhanced skin penetration. While microfluidic methods have enabled controlled liposome synthesis, achieving efficient production of ultrasmall nanoliposomes (NLP_US) with a size smaller than 40 nm yet remains an unmet challenge. Methods: In this study, we employed a helical-blade-strengthened co-flow focusing (HBSCF) device to efficiently synthesize NLP_US, which demonstrated superior skin permeation and retention. Results: Liposome formulation primarily contains unsaturated lecithin, which endows an unprecedented capacity to NLP_US to scavenge reactive oxygen species (ROS). Moreover, NLP_US can effectively encapsulate a broad spectrum of anti-aging agents, including coenzyme Q10 (CoQ10), while preserving its physical properties. In a photoaged skin model, topical application of CoQ10-loaded NLP_US (CoQ10@NLP_US) inhibited ultraviolet B (UVB)-induced matrix metalloproteinase-1 (MMP-1) production, and promoted collagen type I (Col-I) synthesis in skin cells, thereby effectively rejuvenating the photoaged skin. Conclusions: This study presents a straightforward and efficient method for the production of NLP_US, thereby offering a promising platform for transdermal delivery of diverse therapeutic agents.

Sonodynamic therapy (SDT) is a promising treatment modality for breast cancer; however, its effectiveness is often impeded by the hypoxic tumor microenvironment owing to an insufficient oxygen supply in the solid tumors. To overcome this challenge, we elaborately developed a 4T1 tumor-targeted multifunctional nanoagent by integrating both dendrimer-structured copper chelating agents and organic sonosensitizers (IR820) into a biotin-modified nanoliposome via a microfluidic-assisted self-assembly. In particular, the aforementioned copper chelating agent was constructed by introducing multiple xanthate groups into a dendrimer polymer, which showed a significant selectivity for the consumption of the intracellular copper levels. Based on this, the nanoliposome-based therapeutic not only disrupted the activity of the mitochondrial complex IV to directly inhibit the tumor cell proliferation but also suppressed the resistance to the SDT via inhibition of the oxygen consumption for cellular respiration. Both in vitro and in vivo studies confirmed that the designed nanoagents exhibit a synergistic tumor inhibition effect of copper consumption and IR820-mediated SDT. Taken together, this approach establishes a proof-of-concept for the construction of a copper-ion-modulated nanomedicine to significantly enhance the efficiency of oxygen-dependent cancer treatments.

Metal-organic frameworks (MOFs) hold promise as theranostic carriers for atherosclerosis. However, to further advance their therapeutic effects with higher complexity and functionality, integrating multiple components with complex synthesis procedures are usually involved. Here, we reported a facile and general strategy to prepare multifunctional anti-atherosclerosis theranostic platform in a single-step manner. A custom-designed multifunctional polymer, poly(butyl methacrylate-co-methacrylic acid) branched phosphorylated beta-glucan (PBMMA-PG), can effectively entrap different MOFs via coordination, simultaneously endow the MOF with enhanced stability, lesional macrophages selectivity and enhanced endosome escape. Sequential ex situ characterization and computational studies elaborated the potential mechanism. This facile post-synthetic modification granted the administered nanoparticles atherosclerotic tropism by targeting Dectin-1+ macrophages, enhancing in situ MR signal intensity by 72 %. Delivery of siNLRP3 effectively mitigated NLRP3 inflammasomes activation, resulting a 43 % reduction of plaque area. Overall, the current study highlights a simple and general approach for fabricating a MOF-based theranostic platform towards atherosclerosis conditioning, which may also expand to other indications targeting the lesional macrophages.

Ionotropic gelation is widely used to fabricate targeting nanoparticles (NPs) with polysaccharides, leveraging their recognition by specific lectins. Despite the fabrication scheme simply involves self-assembly of differently charged components in a straightforward manner, the identification of a potent combinatory formulation is usually limited by structural diversity in compound collections and trivial screen process, imposing crucial challenges for efficient formulation design and optimization. Herein, we report a diversity-oriented combinatory formulation screen scheme to identify potent gene delivery cargo in the context of precision cardiac therapy. Distinct categories of cationic compounds are tested to construct RNA delivery system with an ionic polysaccharide framework, utilizing a high-throughput microfluidics workstation coupled with streamlined NPs characterization system in an automatic, step-wise manner. Sequential computational aided interpretation provides insights in formulation optimization in a broader scenario, highlighting the usefulness of compound library diversity. As a result, the out-of-bag NPs, termed as GluCARDIA NPs, are utilized for loading therapeutic RNA to ameliorate cardiac reperfusion damages and promote the long-term prognosis. Overall, this work presents a generalizable formulation design strategy for polysaccharides, offering design principles for combinatory formulation screen and insights for efficient formulation identification and optimization.