Inhibition of SerpinB9 to enhance granzyme B-based tumor therapy by using a modified biomimetic nanoplatform with a cascade strategy.

Granzyme B (GrB) is a pivotal killer factor in immunotherapy whose application is limited by hyposensitivity and unsatisfactory cellular uptake by tumor cells. In this study, it was proved that SerpinB9 (Sb9) downregulation can enhance the GrB susceptibility of tumor cells. Moreover, a nanocarrier fused with M1 macrophage exosomes (M1 Exo) and photothermal sensitive liposomes was constructed to efficiently transport GrB and siRNA of Sb9 to the cells. The nanocarrier is characterized by cascade tumor targeting acquired by photothermal effect-triggered increased expression of vascular cell adhesion molecule-1 (VCAM-1) in tumor tissue. Furthermore, the innate cytokines in M1 Exo are capable of regulating the tumor microenvironment by repolarizing M2 macrophages to the M1 type. Collectively, the multifunctional nanoplatform (S+G@ELP) enhances the lethality of GrB to tumor cells, activates a widespread immune response uniting with photothermal therapy (PTT), restrains the tumor progression and metastasis effectively, which is expected to provide new insights into GrB-based combinational tumor therapy.

A cascade synergetic strategy induced by photothermal effect based on platelet exosome nanoparticles for tumor therapy.

Biomimetic drug delivery systems offer new opportunities to mimic biological components for enhancing tumor targeting efficiency and promoting therapeutic efficacy. Therefore, in this study, the platelet exosomes and photothermal sensitive liposomes were coalesced and incorporated glucose oxidase (GOx, G) and ferric ammonium (FAC, F) to constitute a laser controlled nanosystem (FG@PEL). Results confirmed that FG@PEL possessed two cascade therapeutic strategies. As the first cascade therapeutic strategy, FG@PEL had achieved cascade targeting effect due to the inheritance of biological property of platelet exosomes to adhere cancer cells and respond on the vascular damage triggered by photothermal effect. Subsequently, GOx was used to oxidize glucose to produce hydrogen peroxide which could be catalyzed by FAC to realize cascade reaction for enhancing chemodynamic therapy (CDT). Meanwhile, photothermal effect could accelerate the reaction rate to further improve the therapeutic effect by producing more hydroxyl radicals. So significant therapeutic effect could be acquired through the synergistic modality of FG@PEL, and the mechanism of mutual promotion among different treatment was also clarified. Hence, this research may provide a promising strategy for curative tumor therapy.

A cascade targeting strategy based on modified bacterial vesicles for enhancing cancer immunotherapy.

BACKGROUND: As an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application. RESULTS: Herein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuated Salmonella outer membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody. CONCLUSIONS: Interesting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing "vaccine effects", conclusively highlighting its potential in preventing tumor recurrence and improving prognosis.

A splenic-targeted versatile antigen courier: iPSC wrapped in coalescent erythrocyte-liposome as tumor nanovaccine.

The major obstacles for tumor vaccine to be surmounted are the lack of versatile property and immunity-inducing effectiveness. Induced pluripotent stem cells (iPSCs) expressed various antigens the same as multiple types of tumors, providing a promising source of wide-spectrum cancer vaccines. The damaged erythrocyte membrane entrapped by spleen could be developed as antigen deliverer for enhancing acquired immunity. Here, the modified lipid materials were used to dilate erythrocyte membrane to fabricate coalescent nanovector, which not only preserved the biological characteristics of erythrocyte membrane but also remedied the defect of insufficient drug loading capacity. After wrapping iPSC protein, the nanovaccine iPSC@RBC-Mlipo exhibited obvious splenic accumulation, systemic specific antitumor immunity evocation, and effective tumor expansion and metastasis inhibition in mice. Hence, our research may provide a prospective strategy of efficient tumor vaccine for clinical practice.