Xiaoyan He

In solid tumors, communication between dendritic cells (DCs) and T cells is impaired by poor immune infiltration and lack of physical contact, limiting current immunotherapies. Here, we develop a bispecific immune-bridging platform (NVMB) to address these limitations. NVMB consists of tumor cell membrane-derived nanovesicles enriched with damage-associated molecular patterns (DAMPs) that activate DCs and support T-cell responses. The vesicle surface is further functionalized with two aptamers targeting DCs and CD8+ T cells, respectively, thereby enhancing their spatial proximity and facilitating functional DC–T cell interactions. This biomimetic design combines colloidal stability with programmable surface functionalization. Mechanistically, NVMB promotes DC–T interactions and enhances activation-associated phenotypes in both cell populations. In multiple immunocompetent mouse tumor models, NVMB suppresses tumor growth, increases intratumoral accumulation of mature DCs and activated CD8+ T cells, and reshapes the tumor microenvironment transcriptome toward enhanced antitumor immune responses. Moreover, combination with immune checkpoint blockade (ICB) further improves antitumor efficacy compared with either monotherapy, supporting the potential of NVMB as a complementary strategy for enhancing ICB responses. In patient-derived cocultures of circulating tumor cells (CTCs) and autologous peripheral blood mononuclear cells (PBMCs), NVMB enhances T-cell-mediated clearance of CTCs. These findings support NVMB as a stable and modular nanoplatform that integrates immunogenic signaling with immune-cell spatial coordination, providing a promising strategy for strengthening antitumor immunity and improving the efficacy of existing immunotherapies.

Biomimetics is an interdisciplinary field that involves studying the structures, functions, principles, and behaviors of biological systems to draw inspiration and apply this knowledge to technological innovation and engineering design, thereby addressing complex challenges. Biomimetic nanomedicine represents a specific application of biomimetics within the realm of nanomedicine, where biological components are mimicked to construct sophisticated nanodrug delivery systems. These biomimetic nanosystems exhibit multiple unique advantages, including targeted delivery to cells within the tumor microenvironment (TME), prolonged in vivo circulation time, enhanced antigen/adjuvant loading capacity, and high biocompatibility. These properties collectively enhance the efficacy of chemotherapy, radiotherapy, immunotherapy, and photodynamic therapy (PDT) by improving tumor‐specific targeting and reducing off‐target toxicity, thereby establishing biomimetic nanomedicines as a promising platform for reprogramming the TME. This review highlights the categorization, design principles, and manufacturing strategies of biomimetic nanodrugs, providing a systematic review of the interplay between the TME and biomimetic nanomedicines, and elucidating how their interaction potentiates tumor‐killing efficacy. Despite encouraging progress in biomimetic nanomedicines, challenges remain in their clinical translation, including biosafety concerns, scalable manufacturing processes, and optimal drug delivery efficiency. Advances in nanotechnology and precision engineering offer promising avenues for developing personalized biomimetic nanomedicines.

Understanding and modulating the interplay between cancer cells and immune cells is critical for deciphering cancer progression and developing effective therapies. However, studying this interplay using patient-derived cells in animal models remains challenging, and the inherent heterogeneity of human tumors adds complexity to traditional approaches. Here, we demonstrate that functional delivery systems targeting heterogeneous malignant cells enable precise immune modulation and real-time assessment of cancer-immune interactions. By developing a delivery vector that specifically targets circulating malignant cells (CMCs) in patient blood samples, we established an ex vivo platform to study the dynamic interplay between patient-derived cancer cells and immune cells. Using a biomacromolecule-based delivery vector functionalized with the ME07 aptamer with high affinity for multiple subtypes of epidermal growth factor receptor (EGFR), we achieved efficient delivery of the genome editing plasmid and molecular beacons (MBs), enabling EGFR knockout to reverse tumor immunosuppression and in situ mRNA probing in heterogeneous malignant cells. EGFR knockout downregulates both wild-type and mutant EGFR, leading to a reduction in PD-L1 expression. Visualization of the interplay between CMCs and peripheral blood mononuclear cells (PBMCs) shows that edited CMCs with low EGFR and PD-L1 expression become susceptible to immune-mediated clearance, while unedited CMCs with higher EGFR and PD-L1 expression can resist immune attack. After coincubation with edited CMCs, the proportions of CD8+CD69+ and CD8+CD44+ T cells significantly increase, while the proportion of CD4+Foxp3+ T_regs notably decreases, indicating the restoration of immune responses. Our study outlines a methodology for precise evaluation of therapeutic interventions at single-cell resolution, advancing personalized cancer therapy.

Background: Inflammation is a key driver of various liver diseases. NLRP3 inflammasome in hepatic macrophages is a key mediator of inflammation and has emerged as a promising target. Genome editing presents a powerful approach to modulate inflammation by directly disrupting genes such as NLRP3 directly. However, efficient and cell-specific delivery of CRISPR/Cas9 ribonucleoproteins (RNPs) remains challenging.

Compared to tissue biopsy, blood biopsy offers significant advantages in terms of safety and convenience. However, achieving accurate blood biopsy for cancer pathological diagnosis presents substantial challenges. Herein, we have developed a precision blood biopsy technology utilizing a malignant cell-targeted nanoprobe for lung cancer diagnosis. The nanoprobe functionalized with SYL3C-conjugated hyaluronic acid and the KALA-GE11 peptide can efficiently deliver the loaded molecular beacons into heterogeneous circulating malignant cells (CMCs) in whole blood to detect diverse intracellular mRNA markers, including the proliferation marker Ki67, the oncogenic marker c-Myc, and thyroid transcription factor 1 (TTF-1) typically expressed in specific types of lung cancers. The simultaneous detection of various markers not only reduces false-negative rates caused by the high heterogeneity of CMCs but also provides accurate insight into the specific heterogeneity of CMCs for individual patients. The nanoprobe can differentiate lung adenocarcinoma (LAD) and small cell lung cancer (SCLC) from squamous cell carcinoma (SCC). TTF-1 is abundant in CMCs of LAD and SCLC but is relatively less common in SCC. c-Myc is more frequently overexpressed in CMCs from LAD and SCLC. Notably, Ki67 is upregulated in most CMCs across all lung cancer types. Furthermore, this approach can sensitively identify malignant cells from early stage lesions clinically classified as noninvasive carcinoma in situ. This technique holds significant clinical potentials for the early detection and precise characterization of lung cancer. Importantly, this strategy is adaptable for detecting other biomarkers, thereby extending its applicability to the diagnosis of various cancer types.