Brain tumor incidence shows an upward trend in recent years; brain tumors account for 5% of adult tumors, while in children, this figure has increased to 70%. Moreover, 20%-30% of malignant tumors will eventually metastasize into the brain. Both benign and malignant tumors can cause an increase in intracranial pressure and brain tissue compression, leading to central nervous system (CNS) damage which endangers the patients' lives. Despite the many approaches to treating brain tumors and the progress that has been made, only modest gains in survival time of brain tumor patients have been achieved. At present, chemotherapy is the treatment of choice for many cancers, but the special structure of the blood-brain barrier (BBB) limits most chemotherapeutic agents from passing through the BBB and penetrating into tumors in the brain. The BBB microenvironment contains numerous cell types, including endothelial cells, astrocytes, peripheral cells and microglia, and extracellular matrix (ECM). Many chemical components of natural products are reported to regulate the BBB microenvironment near brain tumors and assist in their treatment. This review focuses on the composition and function of the BBB microenvironment under both physiological and pathological conditions, and the current research progress in regulating the BBB microenvironment by natural products to promote the treatment of brain tumors.

Dysregulated epigenetic modifications dynamically drive the abnormal transcription process to affect the tumor microenvironment; thus, promoting cancer progression, drug resistance, and metastasis. Nowadays, therapies targeting epigenetic dysregulation of tumor cells and immune cells in the tumor microenvironment appear to be promising adjuncts to other cancer therapies. However, the clinical results of combination therapies containing epigenetic agents are disappointing due to systemic toxicities and limited curative effects. Here, the role of epigenetic processes, including DNA methylation, post‐translational modification of histones, and noncoding RNAs is discussed, followed by detailed descriptions of epigenetic regulation of the tumor microenvironment, as well as the application of epigenetic modulators in antitumor therapy, with an emphasis on the epigenetic‐based advanced drug delivery system in targeting the tumor microenvironment.

Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance. Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy. Recently, through modulating cancer-associated fibroblasts (CAFs) which are the most abundant cell type among all stromal cells, natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells, showing promising ability to improve treatment effects on desmoplastic tumors. In this review, we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products, highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.

Targeted treatment of cerebral ischemia/reperfusion injury (CIRI) remains a problem due to the difficulty in drug delivery across the blood–brain barrier (BBB). In this study, we developed Bo-TSA-NP, a novel tanshinone IIA (TSA) loaded nanoparticles modified by borneol, which has long been proved with the ability to enhance other drugs’ transport across the BBB. The Bo-TSA-NP, with a particle size of about 160 nm, drug loading of 3.6%, showed sustained release and P-glycoprotein (P-gp) inhibition property. It demonstrated a significantly higher uptake by 16HBE cells in vitro through the clathrin/caveolae-mediated endocytosis and micropinocytosis. Following intranasal (IN) administration, Bo-TSA-NP significantly improved the preventive effect on a rat model of CIRI with improved neurological scores, decreased cerebral infarction areas and a reduced content of malondialdehyde (MDA) and increased activity of superoxide dismutase (SOD) in rat brain. In conclusion, these results indicate that Bo-TSA-NP is a promising nose-to-brain delivery system that can enhance the prevention effect of TSA on CIRI.

A novel oral drug delivery system, TPGS modified docetaxel proniosomes (DTX-TPGS-PNs), was designed to enhance the oral bioavailability and antitumor efficiency of the poorly water-soluble drug docetaxel. DTX-TPGS-PN niosomes were 93 ± 6.5 nm in size, −18.53 ± 1.65 mV in zeta potential and exhibited spherical morphology, with an encapsulation efficiency of 97.31 ± 0.60%. The system showed sustained release in both simulated gastric and intestinal fluid. The results of caco-2 monolayer, everted gut sac model and improved single-pass intestinal perfusion model transport studies showed that DTX-TPGS-PN niosomes could significantly improve the absorption of DTX. The pharmacokinetics study suggested the absolute bioavailability of DTX-TPGS-PN niosomes were 7.3 times that of DTX solution. In addition, a higher antitumor efficacy than DTX solution was demonstrated in MCF-7 and MDA-MB-231 cellsin vitroand in MCF-7 tumor-bearing mice modelin vivo. Our results demonstrated DTX-TPGS-PN is promising in enhancing the bioavailability and efficiency of poorly water-soluble drug DTX, and the potential of proniosomes as stable precursors for oral drug delivery.