Thrombopoietin Mitigates Neuronal Death by Enhancing Mitophagy and Suppressing NLRP3 Inflammasome Activation Under Oxygen-Glucose Deprivation Conditions.

Thrombopoietin (TPO), a principal hematopoietic cytokine, regulates the development and proliferation of megakaryocytes and platelets. Our previous research demonstrated TPO's neuroprotective role against hypoxic-ischemic brain injury in rats. Yet, the underlying mechanisms remain unclear.

Pre-silencing of TNF-α by targeted siRNA delivery mitigates glucocorticoid resistance of dexamethasone in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory autoimmune disease marked by relentless synovial inflammation and joint destruction, for which long-term remission remains challenging. Although dexamethasone (DEX) is commonly employed to rapidly control disease activity, its therapeutic effectiveness is often undermined by the development of glucocorticoid resistance (GCR) and cumulative systemic toxicities. Recent insights suggest that TNF-α-driven inflammation not only perpetuates joint pathology but also sustains a molecular landscape that favors GCR, underscoring an urgent need for therapeutic strategies that jointly target inflammatory signaling and steroid sensitivity.

Long-Acting In Situ Cancer Vaccines by Oncolytic STING-Activating Microgels.

In situ cancer vaccines exploiting endogenous multiple antigens directly from tumors to elicit broad immune responses hold great potential in cancer treatment. However, the feeble antigen presentation and hostile immune microenvironments pose severe challenges to acquiring clinical benefits. Here, oncolytic STING-activating microgels (OSAM) that release oncolytic peptide LTX-315 and STING adjuvant diABZI in a sustained manner (>4 weeks) have been developed to elicit long-acting and powerful antitumor immunity.

Advances and Challenges in Targeted Therapy and Its Combination Strategies for Leukemia.

Leukemia is a group of hematological malignancies with a complex pathogenesis and diverse clinical manifestations. Although traditional treatments such as chemotherapy, radiotherapy, and hematopoietic stem cell transplantation have improved patient outcomes, their efficacy is often limited by non-specificity, drug resistance, and relapse. In recent years, targeted therapy has emerged as a major breakthrough, offering new opportunities for precision medicine in leukemia.

Oral microbiota-regulating and inflammation-targeted polymersome-hydrogels for RNAi therapy of ulcerative colitis.

The treatment of ulcerative colitis is harassed by its intricate pathogenesis and the harsh gastrointestinal environment. Herein, oral microbiota-regulating and inflammation-targeted polymersome-hydrogels are developed by incorporating gallic acid and tumor necrosis factor α-specific siRNA-encapsulated polymersomes (GA-siTNFα-PS) into self-healable and eatable hydrogels (SHE-Gel) formed from thiolated sodium alginate and dopamine-modified oxidized inulin (DA-OIn) for oral RNAi therapy of ulcerative colitis. SHE-Gel is stable in stomach, resides in the intestine, and degrades in the colon by colon-specific inulinase.

Naphthalene-containing octreotide radioligand elevates selectivity and radionuclide therapy for somatostatin receptor 2-positive tumor.

Peptide receptor radionuclide therapy (PRRT) with proven targeting ability has emerged as a new paradigm for clinical tumor therapy. The selective binding of octreotide to somatostatin receptor 2 (SSTR2) renders the successful development of Lu-DOTATATE for SSTR2-positive neuroendocrine tumor patients. Here, we find that naphthalene-containing octreotide radioligand (OCT(naph)) induces elevated tumor uptake and radionuclide therapy for SSTR2-positive tumor over DOTATATE.

Tumor vessel-adaptable adhesive and absorbable microspheres for sustainable transarterial chemoembolization therapy.

Transarterial chemoembolization (TACE) is a common clinical intervention used for unresectable liver tumors, but conventional embolic microspheres generally exhibit slack vascular stacking and suboptimal drug release. Here, we report tumor vessel-adaptable, adhesive, and absorbable microspheres (3Asphere) based on hyaluronic acid developed using microfluidic and radical polymerization techniques for sustained TACE therapy of liver tumors. 3Asphere presents uniform sizes, gradual degradation over two months, and fast encapsulation and sustained release of chemotherapeutics such as epirubicin, irinotecan, and cisplatin.

Oncolytic microgels with regulated antibody release augment tumor immunotherapy.

The inhibition of immune checkpoints has emerged as a most successful immunotherapy strategy for cancers; however, it bears a modest clinical response rate and certain cases severe systemic adverse reactions. Here, oncolytic microgels (OMG) that possess similar antitumor activity and immune activation to oncolytic peptide LTX-315 and are capable of sustained release of immune checkpoint inhibitors have been developed to potentiate cancer immunotherapy. Of note, antibodies including anti-PD-1, anti-PD-L1, and anti-CTLA-4 all could be quantitatively loaded into OMG while being gradually released over a couple of weeks in vitro and in tumor as well.

Liposomal all-trans retinoic acid boosts anti-tumor immunity of radiotherapy via mitigating cancer stemness and remedying tumor microenvironment.

Radiotherapy (RT) induces immunogenic cell death but also promotes immunosuppression, cancer stemness and immune evasion, thus compromising anti-tumor immune response and leading to cancer recurrence and metastasis. Here, we developed liposomal all-trans retinoic acid nanoparticles (LATRA) to simultaneously mitigate cancer stemness and remedy suppressive tumor microenvironment, which on one hand decreases tumorigenicity and sensitizes tumors to RT and on the other hand stimulates dendritic cell maturation and reprograms macrophages toward a pro-inflammatory M1 phenotype. In murine colorectal tumor model, RT combined with LATRA essentially reduces tumor burden, prevents recurrence and induces a durable immune response with memory effects.

DNA damage repair inhibitors boost targeted radionuclide therapy and immunotherapy of prostate cancer.

Targeted radionuclide therapy (TRT) has emerged as a valuable treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. The radioresistance coupled with heterogeneity and immunosuppressive tumor microenvironment of mCRPC, however, greatly restricts the clinical response and anticancer immunity. Here, we found that DNA damage repair inhibitors, in particular ATM inhibitor (ATMi), effectively boost TRT and immunotherapy of prostate cancer.

Nano-golden adjuvant-polymersomes empower tumor photothermal-immunotherapy.

The integration of photothermal therapy with immunotherapy represent a potential treatment for tumor patients. Here, we demonstrate that nano‑golden adjuvant-polymersomes (nGAP) with gold nanoclusters imbedded in the membrane and immunoadjuvant poly(I:C) encapsulated within the aqueous core empower tumor photothermal-immunotherapy. Upon near-infrared irradiation, nGAP elicits a strong photothermal effect on tumor cells, driving immunogenic cell death and activating dendritic cells.

In situ generation of anti-leukemia vaccine by immunogenic dual-drug nanomedicine and polymersomal CpG nanoadjuvant.

Acute myeloid leukemia (AML) is difficult to treat because of the difficulty in completely removing leukemia cells. Therapeutic vaccines that show promise in curing different cancers have achieved relatively little progress in the treatment of AML. Herein, we report the facile in situ generation of an anti-AML vaccine via an immunogenic vincristine/volasertib dual-drug nanomedicine (nanoVi/Vo) and a polymersomal CpG immunoadjuvant (nanoCpG).

D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.

Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism.

Intranasal and Intravenous Sequential Administration of Survivin Peptide-CpG Nanovaccines Elicits Potent Immunity Toward Glioblastoma.

Peptide vaccines hold great promise for treatment of glioblastoma (GBM), though their efficacy remains suboptimal due to factors such as immunosuppressive tumor microenvironment, poor accessibility to tumor site and inadequate activation of antigen-presenting cells. Here, this work reports on survivin peptide-CpG oligodeoxynucleotide (ODN) nanovaccines (SPOD-NV), which feature antigen peptides strategically displayed on polymersomes with CpG ODN encapsulated as an immunostimulatory adjuvant. Sequential administration via intranasal and intravenous routes elicits robust immune response against murine GBM.

Antibody-mediated ratiometric delivery of FLT3 and CDK4/6 dual inhibitors for targeted treatment of acute myeloid leukemia.

Molecularly targeted agents have revolutionized the paradigm of cancer treatment; however, their efficacy is often downplayed by rapid clearance in vivo, inferior cellular delivery and drug resistance. The combination of targeted drugs could improve the clinical efficacy only to some extent, due to overlapping toxicities and difficulty in maintaining certain drug ratios. Here, we report on ratiometric codelivery of FLT3 and CDK4/6 dual inhibitors, gilteritinib and palbociclib, by daratumumab-decorated polymersomes (GIPA@DP) for high-efficacy targeted therapy of acute myeloid leukemia (AML).

In situ therapeutic vaccines for leukemia by chemo-nanoadjuvant therapy.

Therapeutic vaccines introduce a potentially ultimate cure for cancers including leukemia. The personalized vaccines relying on neoantigens though exhibiting clinical benefits are afflicted by long and delicate manufacture procedure, high cost, and possibly incomplete coverage of heterogeneous tumor cells. Here, we report a facile strategy to generate potent in situ therapeutic vaccines, which effectively eliminate leukemia and induce long-term anti-leukemia immunity, by homoharringtonine-nano-dual-adjuvant (HHT-NDA) therapy.

Vincristine/Volasertib polymersome injection enables high-efficiency synergistic treatment of acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), one of the most frequently diagnosed malignancies in children, is associated with a high relapse rate and drug resistance, even with intensive multidrug chemotherapy regimens. The rational combination with molecular targeted agents holds promise for sensitizing patients to chemotherapies and overcoming drug resistance. However, precise codelivery of different drugs in vivo is challenging, often leading to suboptimal therapeutic effects.

Sustained codelivery of heat shock protein peptide and rapamycin via nano-in-hydrogel induces immune tolerance in rheumatoid arthritis.

Co-delivery of autoantigens with immunomodulators via nanovaccines presents a promising strategy for inducing tolerogenic immune responses in rheumatoid arthritis (RA). Conventional subcutaneous administration often results in rapid systemic dissemination, limiting efficacy in targeting lymphatic tissues. Here, we developed a tolerogenic nanovaccine-in-hydrogel delivery system comprising heat shock protein peptide-coated, rapamycin-encapsulated polymeric vesicles (HRV@gel) designed for sustained exposure to lymph nodes.

Brain-targeted polymersomes mediating RNAi of STAT3 sensitize glioblastoma to temozolomide and immunotherapy.

Glioblastoma (GBM) is among the most aggressive brain tumors, presenting significant therapeutic challenges due to intrinsic and acquired resistance to treatment, alongside a highly immunosuppressive tumor microenvironment (TME). While temozolomide (TMZ) is the standard chemotherapeutic agent with the ability to penetrate the blood-brain barrier (BBB), its clinical efficacy is often limited. Here, we report a strategy employing Apolipoprotein E (ApoE) peptide-functionalized polymersomes loaded with small interfering RNA (siRNA) targeting signal transducer and activator of transcription 3 (Apstat3) to amplify the anti-GBM effects of TMZ and immunotherapy.

Polymersome-enabled brain codelivery of STAT3 siRNA and CpG oligonucleotide boosts chemo-immunotherapy of malignant glioma.

Malignant glioma represents one of the most aggressive primary tumors of the central nervous system. The immunotherapy of glioma is restrained by low immunogenicity, an immunosuppressive environment, and challenges in delivering therapeutics and immune-modulating agents. Here, we demonstrate that the systemic brain codelivery of STAT3 siRNA and CpG oligonucleotide using ApoE peptide-functionalized nano-polymersomes (tNano-S&C) significantly boosts the efficacy of chemo-immunotherapy for malignant glioma when combined with temozolomide (TMZ).

Glioblastoma Cell Lysate and Adjuvant Nanovaccines via Strategic Vaccination Completely Regress Established Murine Tumors.

Tumor vaccines have shown great promise for treating various malignancies; however, glioblastoma (GBM), characterized by its immunosuppressive tumor microenvironment, high heterogeneity, and limited accessibility, has achieved only modest clinical benefits. Here, it is reported that GBM cell lysate nanovaccines boosted with TLR9 agonist CpG ODN (GlioVac) via a strategic vaccination regimen achieve complete regression of malignant murine GBM tumors. Subcutaneous administration of GlioVac promotes uptake by cervical lymph nodes and antigen presentation cells, bolstering antigen cross-presentation and infiltration of GBM-specific CD8 T cells into the tumor.

Photothermal treatment of prostate tumor with micellar indocyanine green and napabucasin to co-ablate cancer cells and cancer stem cells.

Advanced prostate cancer is hassled by relapse and metastasis that are closely associated with cancer stem cells (CSCs). Here, we present micellar indocyanine green and napabucasin (mICG-Nap) that co-ablates cancer cells and CSCs via photothermal therapy (PTT) for the treatment of prostate tumor. mICG-Nap with stable loading of both drugs and favorable size effectively reduced CSC population in RM1-PSMA murine prostate cancer cells and inhibited tumor spheroid formation.

Dual-targeted alpha therapy mitigates prostate cancer and boosts immune checkpoint blockade therapy.

Alpha radionuclide with a high emitting energy and short emitting range has emerged as a new tool for the treatment of advanced tumors; however, its clinical usage stringently depends on delivery vehicle. Here, we report on Sigma-1 receptor and PSMA dual-specific peptide with efficient 225‑actinium labeling (Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. Ac-S1R/PSMA-P with a high specific activity and radiostability exhibited upgraded cell binding and uptake while diminished efflux in RM1-PSMA cancer cells.

Near-Infrared Light-Responsive Immunomodulator Prodrugs Rejuvenating Immune Microenvironment for "Cold" Tumor Photoimmunotherapy.

Light-activatable prodrugs have been applied in precision cancer therapy because of their spatiotemporal controllability and minimal toxic side effects. However, the reported prodrugs were limited by the ultraviolet and visible light regions, which seriously restricted their application in deep tissues. Developing a near-infrared (NIR) light-activatable release system remains a great challenge.