Mechanotherapeutic biomaterials: Overcoming physical barriers to enhance intratumoral drug delivery in solid tumours

Abstract

The clinical translation of nanomedicine for solid tumours remains limited despite substantial advances in biomaterial design and molecular targeting, primarily due to the physical inaccessibility of tumour tissue. Solid tumours exhibit a mechanically abnormal microenvironment characterised by extracellular matrix (ECM) densification, elevated solid stress, increased interstitial fluid pressure (IFP), and dysfunctional vasculature, which collectively establish a transport-limiting system that restricts drug penetration and promotes heterogeneous intratumoral distribution. Within this context, nanomedicine failure is best understood as a transport-limited problem in which physical constraints represent dominant, though not exclusive, determinants of therapeutic outcome. This review presents a mechanotherapeutic framework that integrates tumour mechanics with transport principles to guide biomaterial design and improve intratumoral delivery. Mechanotherapeutic strategies are categorised into three complementary approaches: (i) stiffness-modulating systems that remodel the extracellular matrix, (ii) deformable and penetration-optimised materials that navigate structural constraints, and (iii) pressure-alleviating and vessel-normalising systems that restore transport and perfusion. The framework is further extended to incorporate mechanochemical coupling through the representative reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1), linking mechanical stress with redox and metabolic adaptation and informing responsive biomaterial design. Integration with microdevice-enabled platforms, including microfluidic and tumour-on-chip systems, provides a quantitative and experimentally controllable platform for evaluating transport behaviour and optimising delivery strategies. Key translational challenges and future directions towards integrated and precision mechanomedicine are discussed. Collectively, this mechanotherapeutic framework provides a physically informed and experimentally actionable strategy for overcoming transport barriers and advancing the clinical translation of cancer nanomedicine.