Advanced Drug Delivery Strategies for Overcoming Biological Barriers: Tumor Microenvironment and Blood–Brain Barrier

Therapeutic efficacy for malignancies and neurological disorders is fundamentally restricted by biological barriers, particularly the complex tumor microenvironment (TME) and selective blood-brain barrier (BBB). This review analyzes advanced drug delivery technologies engineered to overcome these obstacles. For TME penetration, stimuli-responsive nanocarriers enable spatiotemporally controlled drug release, while tumor-penetrating peptide functionalized nanoparticles enhance deep tumor diffusion; metal-organic frameworks further facilitate combinatorial therapy via microenvironment-triggered payload release. Regarding BBB transcendence, receptor-mediated transcytosis strategies significantly improve brain uptake, and physical-assisted approaches achieve localized barrier modulation. Bioinspired platforms-notably cell-membrane-coated nanoparticles and exosomes-demonstrate superior immune evasion and tissue-specific accumulation. Despite promising clinical progress exemplified by ANG1005 and focused ultrasound-assisted liposomal doxorubicin, translation challenges persist, including TME heterogeneity, scalable manufacturing complexities, and long-term biosafety. Future development prioritizes multifunctional theranostic systems integrating barrier-remodeling agents, artificial intelligence (AI)-optimized nanocarrier design, and sustainable manufacturing processes. Collectively, these innovations are transforming advanced drug delivery into a core therapeutic paradigm for intractable diseases.