Rising as essentially the most aggressive malignant adults mind tumor, the median lifespan of glioblastoma (GBM) is about 15 months, with lower than 10 % of the 5-year survival, characterised by a poor prognosis [1], [2], [3]. Developments in immunotherapeutic methods have demonstrated outstanding success in numerous most cancers varieties and have emerged as an interesting idea for treating GBM [4]. Neoantigen vaccines goal to elicit T cell responses in the direction of tumor-specific antigen epitopes, representing a promising most cancers immunotherapy [5], [6]. Nonetheless, GBM displays a low tumor mutation burden, leading to diminished immunogenicity of neoantigen vaccines to hinder the efficient T-cell recognition [7], [8]. Attributed to extra full antigen epitopes, customized tumor vaccines (PTVs) can evoke a stronger and extra complete anti-tumor immune response for GBM [9]. PTVs generally want a time-consuming sequencing course of and comprise a restricted variety of epitopes. Not too long ago, customized in situ vaccination has been extensively assessed in each preclinical and medical researches [10], [11], [12], [13], [14]. Distinct from conventional PTVs, customized in situ vaccination primarily based on entire tumor cell lysates from sufferers encompasses all potential tumor-specific epitopes in precept, with out pre-identification of antigens. Alternatively, the native antigen presentation occupies a dominant place within the anti-GBM efficacy of neoantigen vaccines [15]. Among the many main varieties of innate immune sample recognition receptors (PRRs), toll-like receptors (TLRs) are extensively expressed on antigen-presenting cells (APCs). Notably, immune-stimulatory adjuvants facilitate dendritic cells (DCs) recruitment and tumor-specific T cells mobilization by binding to TLRs [16]. Consequently, the technique that’s able to constantly delivering in situ vaccines with excessive immunogenicity and appropriate adjuvants is extremely fascinating. Nonetheless, the problem stays within the mixture technique on account of the immunosuppressive tumor microenvironment (TME) blocking the cancer-immunity cycle [17].
Tumor-associated macrophages (TAMs) account for about 80 % of the immune cell composition throughout the TME of GBM [18], [19]. Notably, M2 TAMs are the principle kind of TAMs in GBM tissue, with the potential to take care of immunosuppression [20]. At the moment, numerous methods requiring extra inducers have been developed to reprogramme TAMs from M2 to M1 kind, whereas the direct immunomodulatory capabilities of nanocarriers are usually ignored [21]. There are latest research that show the plant-derived extracellular vesicles (PDVs) possess the capability to boost the polarization of tumoricidal M1 TAMs [22]. Involved with TAMs, nanoparticles can be quickly phagocytosed, and the engineering modification just like the mannose (MAN) ligand design has been proven to have extra potential for concentrating on TAMs [22], [23]. Subsequently, the engineering modified-PDVs could also be employed to focus on and instantly repolarize TAMs for immunosuppressive TME reversal. Furthermore, the immunosuppression of GBM is additional regulated by irregular metabolism, which is commonly pushed by the over-activated glycolysis [24], [25], [26]. With a serious metabolite, lactic acid (LA) accumulating in TME, glycolysis seems to sign to TAMs for the immunosuppressive M2 phenotype transformation [27]. Apart from, the acidification of TME accelerates the differentiation of regulatory T cells (Tregs), the era of myeloid-derived suppressor cells (MDSCs), and the restraining of T cell activation [28], [29]. Thus, the native supply of metabolism-modulating compounds is taken into account a potential technique for in situ most cancers vaccination. Growing proof confirms that the event of immune cells in TME might be modulated by lowering LA. Nonetheless, merely suppressing LA transport leads to dose-dependent uncomfortable side effects and a sustained accumulation of LA within the metabolic cycle [30]. Catalytic regulation of metabolites, for instance, methods to inhibit the important thing enzymes within the glycolysis course of, similar to hexokinase (HK) and pyruvate kinase (PK), present a possible strategy for reprogramming metabolism and enhancing anti-tumor immunity in TME [31]. Therefore, the mix of engineered nanocarriers regulating TAMs repolarization and TME metabolic reprogramming primarily based on enzymatic catalytic regulation could also be a promising strategy to reverse immunosuppressive TME.
One other bottleneck for neoantigen vaccine utility within the central nervous system (CNS) illness is the extremely regulated and sophisticated boundaries, stopping medicine from reaching the mind goal web site [32]. Systemic and native supply administration routes to the CNS embrace intravenous, oral, intrathecal, and intraparenchymal supply [33]. Whereas the above administration routes are vulnerable to systemic metabolism, poor affected person compliance, and an infection. As a non-invasive strategy, intranasal administration appears to be a fascinating selection to handle these points [34], [35]. Nonetheless, environment friendly nasal absorption for nose-to-brain supply is proscribed by the nasal mucosal epithelial barrier. Subsequently, it’s important so as to add absorption enhancers to boost nasal absorption additional, selling intranasal supply [36]. Furthermore, the ciliary actions, mucus, and detoxifying enzymes may inhibit the nasal absorption [35]. PDVs have proven promise as mucoadhesive carriers for intranasal supply, providing low toxicity and excessive biocompatibility [37], [38]. Whereas the restrictions of PDVs additionally exist, similar to poor stability, low loading effectivity, and restrictive chemical modification choices. Considerably, liposome (Lipo)-based carriers provide the choice to resolve these issues [39], [40], [41]. Subsequently, the intranasal administration of a nano-delivery system primarily based on hybrid vesicles composed of PDVs and Lipo is anticipated to attain native and non-invasive drug supply routes to the CNS.
On this work, we proposed an intranasal hybrid vesicle to ship a personalised in situ nano-vaccine that reversed TME to spice up the anti-GBM immune response of the most cancers vaccine. Muskone (Mus)-modified ginseng-derived nanoparticles (Mus-GDNPs) and Shikonin-encapsulated liposome (Lipo/SKN) had been membrane fused and co-incubated with MAN-modified CpG (mCpG) to acquire intranasal hybrid vesicles (mCpG-MGLPs/SKN) (Scheme 1A). After intranasal administration, the nasal mucosal penetration enhancer Mus promoted the transport of mCpG-MGLPs/SKN to the mind through the olfactory nerve route (Scheme 1B). Subsequently, these nano-vaccines reached the tumor web site, because of the interplay between ginsenoside Rg3 on GDNPs and the GLUT1 on GBM cells. Afterwards, considerable in situ tumor antigens had been generated by SKN-induced immunogenic cell demise (ICD), mixed with immune-adjuvant mCpG to recruit DCs. Moreover, the degrees of glycolytic rate-limiting enzymes PKM2 and HK Ⅱ had been restrained by SKN, successfully inducing the LA depletion. The TAMs’ repolarization in TME was promoted by GDNPs-triggered TLR4/myeloid differentiation antigen 88 (MyD88) pathway activation, secreting pro-inflammatory elements to spice up T cell immunity (Schemes 1C and 1D). Vaccines with superimposed activation alerts exert anti-tumor results primarily via the next mechanisms: 1) By enhancing the DCs’ antigen-presenting, T cells differentiation into CTLs, and tumor-killing cytokines secretion, thus inducing adaptive immunity; 2) By augmenting the phenotypic transformation of TAMs and regulating acidic TME metabolism, thereby inducing innate immunity and reversing the immunosuppressive TME. This design can ship ICD activator and TLR agonist to antigen-capturing cells, synchronously conveying glycolysis inhibitor and TAMs repolarization inducer to TME. Collectively, it offers a multi-pronged strategy for innate and adaptive immune eliciting.
