In the rapidly evolving landscape of cancer research, a fresh interdisciplinary perspective is emerging that challenges long-held assumptions about how tumors grow, communicate, and spread. At the intersection of mechanobiology and extracellular vesicle (EV) biology lies a promising frontier—one where the physical forces governing tissues and the tiny molecular messengers they emit converge to tell a more complete story of cancer progression. Recent work led by Ravi Radhakrishnan, Professor and Department Chair at the University of Pennsylvania’s Bioengineering Department, together with his Ph.D. student Kshitiz Parihar, unveils this dynamic interplay in a landmark literature review published in Nature Biomedical Engineering. Their synthesis offers novel insights into how mechanical environments shape vesicle behavior, and vice versa, reframing cancer as as much a physics problem as a biochemical one.
This review is not a mere catalog of discoveries; it is a conceptual blueprint for the future of mechanobiology applied to oncology. Tumors have long been studied through the lens of altered genetic and chemical signaling pathways, but Radhakrishnan and Parihar propose that understanding the mechanical properties of tumors—stiffness, pressure, and deformation—can reveal hidden layers of regulation that drive malignancy. Mechanical forces influence how cancer cells package and secrete extracellular vesicles, which are nano-scale parcels loaded with proteins, RNA, and lipids. These vesicles traverse the body like cryptic messages, retrievable through minimally invasive procedures such as blood draws, providing invaluable diagnostic information.
The power of EVs as biomarkers stems from their accessibility and their payload, which reflects the molecular identity of their parent cancer cells. Unlike traditional biopsies, which are invasive and often limited in what they can reveal, EVs circulate systemically and offer a dynamic snapshot of tumor activity. Yet the fundamental question remains: What causes cancer cells to secrete dramatically more EVs than normal cells, and how do these vesicles mechanistically alter the tissue microenvironment? Radhakrishnan’s team highlights that the mechanics of the surrounding tissue—its stiffness and stress patterns—could regulate both the quantity and composition of vesicles produced by tumors, indicating a bidirectional communication loop between physical forces and vesicular messaging.
At the core of this hypothesis is the idea that tumors are physically distinct from healthy tissue. Cancerous masses exhibit altered mechanical characteristics—they tend to be stiffer and more heterogeneous in texture. This physical remodeling not only affects cancer cell behavior autonomously but also modulates the release and functional cargo of EVs. Experimental evidence suggests that EVs can reinforce these mechanical changes, actively stiffening distant tissue sites to prime them for metastatic colonization. This crosstalk between mechanics and vesicle biology opens uncharted therapeutic avenues, ranging from targeting vesicle release pathways to engineering EV-based drug delivery systems that can negotiate the body’s most challenging barriers, including the blood-brain barrier.
Innovative collaborations have emerged to explore such possibilities. The Radhakrishnan lab at Penn partners with Jina Ko’s research group and clinical departments to pioneer combination therapies that merge endogenous EVs with engineered lipid nanoparticles. This hybrid drug delivery approach exploits the natural biocompatibility and targeting capacity of vesicles with the customizable features of synthetic nanoparticles, aiming particularly at hard-to-treat cancers such as those of the head and neck. This merger of biology and nanotechnology exemplifies how interdisciplinary mechanobiology can translate from fundamental insights into applied clinical strategies.
The inherent difficulty in studying EVs lies in their minuscule size—often only tens of nanometers—placing them beyond the threshold of many conventional imaging techniques. To circumvent this barrier, computational modeling has emerged as an indispensable tool to capture the dynamics of vesicle trafficking and interactions at cellular and systemic levels. Parihar’s work employs sophisticated simulations validated by experimental data to create virtual maps of vesicle journeys, exploring how they traverse the body, navigate cellular environments, and influence immune responses. These models not only enhance our understanding of cancer dissemination but also guide the design of better therapeutic interventions by predicting how altering vesicle mechanics might impede cancer progression.
Training a new generation of scientists to thrive at this biological and engineering nexus is equally paramount. The Radhakrishnan lab exemplifies a multidisciplinary ecosystem where bioengineers, biologists, computational scientists, and clinicians collaborate seamlessly. This integrative approach ensures that emerging researchers possess the breadth and depth necessary to tackle the complex mechanobiological problems cancer presents. The lab’s educational initiatives emphasize open-minded inquiry, encouraging students to seek connections beyond their immediate disciplines, thereby fostering innovation that could precipitate breakthroughs unforeseen in siloed research environments.
Mechanobiology’s ascendancy in cancer science can be traced back to foundational work at Penn by Wei Guo and colleagues. Their conceptualization that intracellular transport mechanics carry equal weight alongside chemical signaling has galvanized a shift in focus towards how physical properties and molecular trafficking intersect in malignancy. This shift reframes cancer as a holistic problem involving physics, engineering, and biology, demanding integrated methodologies and diverse expertise to unravel its intricacies. Radhakrishnan and his team’s recent review situates their ongoing research within this transformative paradigm, underscoring Penn’s role as a hub for convergent mechanobiology research capable of generating novel diagnostics and treatments.
Looking forward, the horizon is rich with potential. As imaging technologies advance and computational power escalates, researchers anticipate more direct observation of EV dynamics at unprecedented resolutions, which will refine models and hypotheses. Concurrently, therapeutic exploitation of the mechanics–vesicle feedback loop offers a promising route to disrupt tumor progression and metastasis. This conceptual framework moves beyond viewing cancer strictly as a biochemical disease; it embraces a vision where physical forces and biological information flow are equally vital.
By pioneering the integration of tumor mechanics and extracellular vesicle biology, the Penn bioengineering community charts a course toward innovative cancer interventions. Their work not only advances scientific understanding but also inspires new paradigms of interdisciplinary collaboration, education, and treatment development. The implications extend far beyond oncology, signaling a future where mechanobiology informs diverse biomedical challenges, transforming how we perceive and combat disease at the cellular and systemic levels.
Subject of Research: Not explicitly specified
Article Title: Mechanical regulation of extracellular vesicle activity during tumour progression
News Publication Date: August 6, 2025
Web References:
References:
Radhakrishnan, R., Parihar, K., et al. (2025). Mechanical regulation of extracellular vesicle activity during tumour progression. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-025-01446-0
Image Credits: Penn Engineering
Keywords: mechanobiology, extracellular vesicles, tumor mechanics, cancer progression, bioengineering, computational modeling, drug delivery, nanotechnology, metastasis, interdisciplinary research
