Peiqi Zhao

Outer membrane vesicles (OMVs), as promising delivery vectors, have been extensively explored for the delivery of nucleic acid-based drugs, particularly the RNA therapy. However, RNA-loaded OMVs delivery systems derived from in vivo engineered bacteria lack the controllable way for regulating target RNA synthesis. Constitutive RNA synthesis may not only exert excessive metabolic burden on engineered bacteria but also lead to unexpected RNA package and delivery, markedly compromising in vivo biomedical applications. Herein, we developed an optogenetically regulated small interfering RNA (siRNA) synthesis and delivery system based on engineered bacterial OMVs. A proof of concept was demonstrated for combining this optogenetic siRNA delivery system with photothermal therapy (PTT) to evaluate tumor thermal resistance modulation by using dual functional engineered strains. The first strain (opto-siTRPV1@OMVs BL-ves) was designed to secrete siRNA targeting transient receptor potential vanilloid subtype 1 (TRPV1) in response to green light stimulation, while a second melanin-producing strain (BL21-TYR) was established for efficient photothermal ablation under 808 nm near-infrared (NIR) laser irradiation. Experimental results showed that the combined therapeutic regimen demonstrated a preliminary tumor growth inhibition rate of approximately 63.06% in a murine model. Furthermore, this regimen remodeled the immunosuppressive tumor microenvironment (TME), activated antigen-presenting cells, promoted the infiltration of effector T cells, and thereby triggered robust anti-tumor immune responses. This study presents a novel strategy for the precise and regulated delivery of siRNA, and demonstrates the feasibility of optogenetically controlled siRNA production and OMV-mediated delivery in a laboratory setting.

Outcomes in older patients with Hodgkin lymphoma (HL) are compromised by the interplay of patient frailty and disease aggressiveness; however, current stratification tools, including the International Prognostic Score (IPS) and Comprehensive Geriatric Assessment (CGA), lack sufficient prognostic discrimination in the older HL population. We developed and validated a prognostic model integrating metabolic tumor burden and geriatric assessment. In this retrospective study across 14 centers in China between 2006 and 2024, we enrolled 306 patients aged ≥ 60 years with histologically confirmed HL. Patients were randomly partitioned into training ( n = 250) and validation ( n = 56) cohorts. Among the 306 patients, 98 deaths and 130 progression events were recorded during follow‐up. We analyzed 21 candidate variables. The least absolute shrinkage and selection operator (LASSO) analysis and multivariable Cox regression identified five independent predictors for 5‐year overall survival (OS): age > 73 years, baseline 18F‐FDG PET/CT‐derived total lesion glycolysis (TLG) > 200, hemoglobin ≤ 101 g/L, activities of daily living (ADL) dependence, and lymphocyte‐depleted classical Hodgkin lymphoma (LDCHL). A weighted Geriatric Risk Score stratified patients into low‐, intermediate‐, and high‐risk groups. In the validation cohort, the Geriatric Risk Score showed higher discriminatory accuracy than the CGA for both OS (C‐index, 0.770 [95% CI, 0.674–0.867] vs. 0.671 [0.581–0.762]) and PFS (0.761 [0.668–0.853] vs. 0.635 [0.535–0.735]). Among advanced‐stage (Ann Arbor stage III–IV) patients, it also outperformed the IPS‐7 and IPS‐3. By integrating metabolic tumor burden and geriatric assessment, the Geriatric Risk Score improves risk stratification over existing tools in older patients with HL.

Introduction: Tumor vaccines can activate tumor-specific immune responses to inhibit tumor growth, recurrence, and metastasis. However, the efficiency of antigen and adjuvants combined delivery to lymph nodes (LNs) is relatively low, leading to weak immune stimulation and tolerance. In this study, a tumor nanovaccine was constructed for the targeted dendritic cells (DCs)-mediated immunotherapy. Methods: Ovalbumin (OVA) antigen was first loaded into manganese-doped mesoporous silica nanoparticles (MMSNs) and coated with bacterial cytoplasmic membrane (BM), which was further inserted with mannose to prepare OVA@MMSNs@BM-Man nanovaccines. In vitro and in vivo experiments were conducted to assess their properties and function of the synthesized nanovaccines. Results: The nanovaccine can effectively target DCs in LNs by the combination of mannose with mannose receptor (CD205). BM serves as an immune adjuvant and co-delivers with OVA antigen, effectively improving antigen presentation efficiency. In an acidic environment, the Mn²⁺ produced by the degradation of MMSNs can not only serve as an MR imaging agent but also activate the cGAS-STING pathway, followed by the release of IFN-β. The activated DCs further activate the body’s cytotoxic T cells (CTLs), thereby exerting anti-tumor effects. The conclusion: This study will provide a new idea for the construction of tumor nanovaccines.

Polatuzumab vedotin plus R‐CHP (Pola‐R‐CHP) is approved as a new standard first‐line therapy for diffuse large B‐cell lymphoma (DLBCL) based on the POLARIX trial. However, real‐world data on its efficacy and safety in unselected patients is lacking. We conducted a retrospective cohort study to evaluate Pola‐R‐CHP versus R‐CHOP outcomes in routine clinical practice in China. This is a multi‐institutional retrospective cohort study and included all consecutive patients that received at least one dose of polatuzumab vedotin up until February 2024. A total of 600 eligible patients from 6 centers were identified, 131 receiving Pola‐R‐CHP and 469 R‐CHOP. After 1:2 propensity score matching, 128 pairs were obtained for further survival and prognosis analysis. With a median follow‐up of 12.8 months, 12‐month progression‐free survival (PFS) was numerically higher with Pola‐R‐CHP versus R‐CHOP (90.3% vs. 84.1%, p = 0.18). Benefits were consistently observed across molecular subgroups, especially advanced stage, ECOG ≥ 2, extranodal involvement ≥ 2 and non‐GCB group. The complete response rate of the Pola‐R‐CHP group was higher than that of the RCHOP group (86.8% vs. 79.7%; p = 0.09), but there was no statistical difference. Safety profiles were comparable, with no new concerns. Among 128 patients treated with Pola‐R‐CHP, 96 underwent gene sequencing analysis: MCD (25.0%), EZB (13.5%), combined subtype (12.5%), ST2 (9.4%), and other/unclassifiable subtype (30.2%). The most common mutations (> 25% of cases) were PIM1, TP53, BCL‐6, KMT2D, SOCS1, BCL‐2. Genetic testing results show the correlation between genotyping, gene mutations in PIM1/TP53 and therapeutic efficacy. This large real‐world study supports Pola‐R‐CHP as an effective frontline option for DLBCL, with sustained efficacy versus R‐CHOP observed in unselected populations. While 12‐month PFS failed to reach statistical significance, subgroup analyses favor Pola‐R‐CHP. Further research with a wider population, longer follow‐up, and screening of advantageous groups are warranted.

Engineering bacteria can achieve targeted and controllable cancer therapy using synthetic biology technology and the characteristics of tumor microenvironment. Besides, the accurate tumor diagnosis and visualization of the treatment process are also vital for bacterial therapy. In this paper, a light control engineered bacteria system based on upconversion nanoparticles (UCNP)-mediated time-resolved imaging (TRI) was constructed for colorectal cancer theranostic and therapy. UCNP with different luminous lifetimes were separately modified with the tumor targeting molecule (folic acid) or anaerobic bacteria (Nissle 1917, EcN) to realize the co-localization of tumor tissues, thus improving the diagnostic accuracy based on TRI. In addition, blue light was used to induce engineered bacteria (EcN-pDawn-φx174E/TRAIL) lysis and the release of tumor apoptosis-related inducing ligand (TRAIL), thus triggering tumor cell death. In vitro and in vivo results indicated that this system could achieve accurate tumor diagnosis and light-controlled cancer therapy. EcN-pDawn-φx174E/TRAIL with blue light irradiation could inhibit 53% of tumor growth in comparison to that without blue light irradiation (11.8%). We expect that this engineered bacteria system provides a new technology for intelligent bacterial therapy and the construction of cancer theranostics.

Purpose: Cancer vaccines are a promising therapeutic approach in cancer immunotherapy and can inhibit tumor growth and prevent tumor recurrence and metastasis by activating a sustained antitumor immunoprotective effect. However, the therapeutic effect of cancer vaccines is severely weakened by the low immunogenicity of cancer antigens and the immunosuppressive microenvironment in tumor tissues. Methods: Here, we report a novel hybrid membrane nanovaccine, composed of mesoporous silica nanoparticle as a delivery carrier, hybrid cell membranes obtained from dendritic cells and cancer cells, and R837 as an immune adjuvant ([email protected]). We investigated the anti-tumor, tumor recurrence and metastasis prevention abilities of [email protected] and their mechanisms of action through a series of in vivo and ex vivo experiments. Results: [email protected] not only provide effective antigenic stimulation but are also a durable supply of the immune adjuvant R837. In addition, [email protected] promote antigen endocytosis into dendritic cells via various receptor-mediated pathways. Compared with HM-NPs or [email protected], [email protected] in combination with an immune checkpoint blockade showed stronger antitumor immune responses in inhibiting tumor growth, thus eliminating established tumors, and rejecting re-challenged tumors by regulating the immunosuppressive microenvironment and immunological memory effect. Conclusion: These findings suggest that the hybrid membrane nanovaccine in combination with immune checkpoint blockade is a powerful strategy to enhance antitumor immunotherapy without concerns of systemic toxicity.

Neuromodulation is becoming more and more important in studying brain function, disease treatment, and brain–computer interfaces. However, traditional regulation methods cannot effectively achieve both wireless regulation and highly sensitive response, which are essential factors in neuromodulation. In this paper, a “magnetism‐optogenetic” system is constructed, which uses a magnetic field to drive mechanoluminescent materials (ZnS:Cu) to generate light, thus stimulating photogenetic proteins. This system effectively combines the wireless magnetic regulation with the high sensitivity of optogenetics. The results show that the luminous intensity of this system changes with the power of an external magnetic field. In addition, under the continuous stimulation of the wireless magnetic field, this system can activate hippocampal‐related neural responses and induce the expression of C‐fos. In the end, this system can further regulate the movement behavior of rats with C1V1 protein expression in the primary motor cortex. This new magnetism‐optogenetic system will provide an excellent reference for wireless and highly sensitive neuromodulation.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignant disease with a high rate of recurrence and metastasis, few effective treatment options and poor prognosis. Here, we designed and constructed a combined photothermal immunotherapy strategy based on cancer cell membrane-coated biomimetic black phosphorus quantum dots (BBPQDs) for tumor-targeted photothermal therapy and anti-PD-L1 mediated immunotherapy. Results: BBPQDs have good photothermal conversion efficiency and can efficiently target tumor cells through homologous targeting and tumor homing. Under near infrared irradiation, we found that BBPQDs kill tumors directly through photothermal effects and induce dendritic cells maturation. In vivo studies have confirmed that the combined photothermal immunotherapy strategy displays a stronger antitumor activity than anti-PD-L1 monotherapy. In addition, BBPQDs-mediated photothermal therapy in combination with anti-PD-L1 treatment inhibit tumor recurrence and metastasis by reprograming the immunosuppressive tumor microenvironment into an immune-active microenvironment, and promoting the local and systemic antitumor immune response. We further found that the combined photothermal immunotherapy strategy can produce an immune memory effect against tumor rechallenge. Conclusions: This study provides a novel therapeutic strategy for inhibiting the recurrence and metastasis of TNBC, with broad application prospects.

Purpose: Although anti-programmed cell death protein 1 antibody (aPD1) immunotherapy and chemotherapy has made much progress in the treatment of melanoma, the efficacy still needs to be further improved. Methods: Cancer treatment has been greatly enhanced by the use of nanotechnology. Cancer cell membrane (CCM)-camouflaged nanoparticles have shown promising potential in tumor therapy due to their excellent homologous-targeting ability, long blood circulation and immune escape. This work presents a biocompatible and tumor acidic environmental responsive CCM-camouflaged mesoporous silica nanoparticle (CMSN) that is loaded with dacarbazine (DTIC) and combined with aPD1 to achieve better antitumor efficacy. Results: In vitro cell experiments demonstrated that DTIC@CMSN exhibits a better anti-tumor killing efficiency and a stronger ability to promote the apoptosis of tumor cells than free DTIC. In vivo antitumor results demonstrated that combination therapy of DTIC@CMSN chemotherapy and aPD1 immunotherapy remarkably suppress the melanoma growth and prolong survival time due to highly selective tumor killing, activation of tumor-specific T cells, and regulation of the immunosuppressive tumor microenvironment. In addition, safety evaluation studies of DTIC@CMSN also demonstrate their increased tumor accumulation and decreased systemic toxicity. Conclusion: This study provides a promising nano-platform for the combination of chemotherapy with immunotherapy, which is potentially useful for the treatment of melanoma.