Introduction: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal . Areas covered: This review focuses on key brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems. Expert opinion: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.

High-grade gliomas are still characterized by a poor prognosis, despite recent advances in surgical treatment. Chemotherapy is currently practiced after surgery, but its efficacy is limited by aspecific toxicity on healthy cells, tumour cell chemoresistance, poor selectivity, and especially by the blood–brain barrier (BBB). Thus, despite the large number of potential drug candidates, the choice of effective chemotherapeutics is still limited to few compounds. Malignant gliomas are characterized by high infiltration and neovascularization, and leaky BBB (the so-called blood–brain tumour barrier); surgical resection is often incomplete, leaving residual cells that are able to migrate and proliferate. Nanocarriers can favour delivery of chemotherapeutics to brain tumours owing to different strategies, including chemical stabilization of the drug in the bloodstream; passive targeting (because of the leaky vascularization at the tumour site); inhibition of drug efflux mechanisms in endothelial and cancer cells; and active targeting by exploiting carriers and receptors overexpressed at the blood–brain tumour barrier. Within this concern, a suitable nanomedicine-based therapy for gliomas should not be limited to cytotoxic agents, but also target the most important pathogenetic mechanisms, including cell differentiation pathways and angiogenesis. Moreover, the combinatorial approach of cell therapy plus nanomedicine strategies can open new therapeutical opportunities. The major part of attempted preclinical approaches on animal models involves active targeting with protein ligands, but, despite encouraging results, a few number of nanomedicines reached clinical trials, and most of them include drug-loaded nanocarriers free of targeting ligands, also because of safety and scalability concerns.

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “glioblastomas,” “immunotherapies,” and “treatment.” The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient’s body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with “glioblastoma”, “CAR-T”, “T cell therapy”, “overall survival”, and “progression free survival” were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.