Overcoming Physiological Barriers in Brain Tumor Therapy: Advances in Nanomedicine, Ultramolecular Pharmaceuticals, and Targeted Drug Delivery

Targeting brain tumors remains a formidable challenge due to the presence of complex physiological barriers, notably the blood-brain barrier (BBB), the blood-brain tumor barrier (BBTB), and the nose- tobrain barrier. These barriers hinder effective drug delivery, limiting therapeutic efficacy. This review provides a comprehensive analysis of the anatomical and molecular characteristics of these barriers, with particular emphasis on the heterogeneity of the BBTB and its implications for targeted drug transport. A detailed overview of various brain tumor types-including glioblastoma, pediatric brain tumors, and brain metastases—is presented alongside a critical evaluation of existing therapeutic modalities. The review highlights the advancement of ultramolecular pharmaceuticals specifically engineered to circumvent the BBTB, focusing on both transvascular and cell-mediated delivery mechanisms. The role of nanomedicine in modulating the immune response and altering the tumor microenvironment is explored as a promising avenue for enhancing therapeutic outcomes. Particular emphasis is placed on nanogels as a versatile and efficient drug delivery platform. Key fabrication techniques such as precipitation polymerization, emulsion polymerization, self-assembly, and micro-templating methods are thoroughly discussed, alongside strategies for polymer crosslinking to enhance stability and functionality. In addition, the review addresses preclinical evaluation strategies, including in vitro models (e.g., BBB-mimicking systems, tumor spheroids) and in vivo studies in animal models, to assess the safety, biodistribution, and therapeutic efficacy of nanogel-based systems. Finally, current clinical progress, challenges, and future perspectives are presented, underscoring the urgent need for innovative, targeted, and personalized drug delivery approaches. This review aims to guide future research in overcoming delivery obstacles and improving outcomes for patients with brain tumors through the strategic integration of advanced nanotechnology and molecular targeting.