2026 Theses Doctoral

Engineering a Carbon-Based Nanocarrier Platform for the Simultaneous Delivery of Nanobodies and Nucleic-Acid-Based Therapies for Triple-Negative Breast Cancer

Alexander, Elena

Complex, multifactorial diseases, including cancer, cardiovascular, metabolic, and neurodegenerative disorders continue to be primary contributors of global morbidity and mortality. These conditions stem from the intricate interplay of genetic, molecular, environmental, and lifestyle factors, resulting in widespread dysregulation across biological networks and posing significant challenges to effective therapeutic intervention. Intrinsic adaptive responses, including redundant signaling and feedback mechanisms, further complicate treatment outcomes by fostering therapeutic resistance and contributing to systemic toxicities that limit efficacy.

Triple-negative breast cancer (TNBC) exemplifies these challenges. Characterized by the absence of defined molecular targets, TNBC exhibits rapid progression, frequent recurrence, and pronounced resistance to established therapies. Despite advances in targeted and immune-based treatments, patient outcomes remain suboptimal owing to tumor heterogeneity and mechanisms of immune evasion.

To address these barriers, this dissertation introduces a carbon-based nanocarrier platform designed for the simultaneous delivery of an epidermal growth factor receptor-specific nanobody (VHH) and an immunostimulatory double-stranded RNA (dsRNA). This system integrates tumor-specific targeting, immune activation, and a novel nanoparticle synthesis strategy to overcome drug resistance and promote immune-mediated tumor eradication.

Carbon, serving as the structural backbone of biological macromolecules, exhibits remarkable material versatility owing to its sp, sp², and sp³ hybridization states. These configurations provide unique combinations of mechanical strength, electrical conductivity, chemical stability, and biocompatibility, positioning carbon and its derivatives as key materials in nanotechnology and biomedical engineering.

By combining a VHH nanobody and dsRNA within a single carbon carrier, this platform achieves molecular specificity and immune stimulation. Nanobodies offer high affinity, biochemical stability, and deep tissue penetration, enabling precise targeted delivery. Concurrently, dsRNA functions as a viral mimic, activating innate immune pathways and inducing immunogenic cell death. This dual-function approach directly addresses the limitations of conventional monotherapies and establishes a generalizable framework for programmable, multimodal treatment strategies.

A parallel aspect of this work involves overcoming challenges in the reproducibility and clinical translation of carbon-based materials. Conventional top-down synthesis methods often yield heterogeneous particles with uncontrolled defects, resulting from the fragmentation of bulk carbon under extreme conditions. To overcome this, a bottom-up fabrication strategy is defined in which customized carbon precursors are three-dimensionally printed and subsequently transformed using localized femtosecond laser processing. This design-driven approach directly links precursor architecture to the resulting material properties, producing uniform, tunable, and reproducible carbon constructs suitable for biomedical and quantum applications.

Collectively, this dissertation highlights the potential of carbon-based nanocarriers as modular and versatile platforms for the management of multifactorial diseases. By integrating precision synthesis methods with immunomodulatory strategies, this research seeks to advance personalized medicine and foster transformative progress across the biomedical, quantum, and material sciences. Ultimately, the work presented herein offers a blueprint for next-generation therapeutic vehicles that enhance efficacy, safety, and personalization, while highlighting the transformative potential of nanotechnology to revolutionize precision medicine through the creation of intelligent, multifunctional platforms.