Comprehensive analysis of the influence of physicochemical properties and tumor-associated environments on liposome intratumoral penetration

Poor tumor penetration is the most significant barrier to the clinical translation of nanomedicines. Despite numerous studies, little is known about how the physicochemical properties and tumor-associated environments impact liposome intratumoral penetration from a multi-factorial perspective. Thus, we developed a set of model liposomes to explore the laws of their intratumoral penetration. Our comprehensive analysis revealed that zeta potential, membrane fluidity, and size of liposomes could influence their penetration in the peripheral, intermediate, or central areas of the tumor, respectively. Moreover, protein corona and stromal cells primarily impeded liposome penetration in the tumor periphery, while the vascular vessels had a similar effect in the tumor center. Our results also revealed a non-monotonic relationship, indicating that the best condition for a single factor may not necessarily be the optimal choice when considering all the factors. The preferred size, zeta potential, and membrane fluidity for excellent tumor penetration are within the ranges of 52–72 nm, 16–24 mV, and 230–320 mp, respectively. Our study provides a comprehensive understanding of the influence of physicochemical properties and tumor-associated environments on liposome intratumoral penetration, offering explicit guidance for the precise design and rational optimization of anti-tumor liposomes.