Bioengineering Exosomes for Tumor Targeting: How Many Can We Conquer?

Exosomes, nature’s own nanocarriers, are rapidly emerging as a disruptive platform for precision oncology. This symposium will focus on innovative strategies to bioengineer exosomes that selectively target two key proteins frequently exploited by tumor cells: programmed cell death ligand 1 (PD-L1) and trophoblast cell surface antigen 2 (Trop2). By pushing the boundaries of molecular engineering, these next-generation exosomes can be functionalized to (1) deliver potent therapeutic cargos directly to tumor cells, (2) modulate the tumor microenvironment, and (3) orchestrate a stronger immune response against cancer. Further, by simultaneously blocking PD-L1-mediated immune evasion and deliver STAT3 siRNA, significantly lowering resistance in triple-negative breast cancer leading to significantly reduced tumor progression in vivo. Novel surface engineering approaches, including high-precision membrane modifications and advanced ligand display, enable robust, multivalent targeting of PD-L1, greatly enhancing specificity and therapeutic uptake in resistant tumor cells. Complementary breakthroughs in Trop2 nanobody-decorated exosomes will also be showcased. These nanovesicles exhibit remarkable binding affinity for Trop2-overexpressing tumors, driving down tropism for metastatic niches while disrupting oncogenic signaling pathways—reducing phosphorylated ERK, cyclin D1, and phosphorylated STAT3, among others. Intriguingly, this strategy also spares healthy tissues, offering a leap forward in minimizing off-target effects.

In addition, emerging data suggest synergistic immune effects, with Trop2-targeted exosomes reducing pro-tumor cytokines (e.g., IL-6) and boosting T cell-supportive cytokines like IL-2, heralding a possible “one-two punch” of direct tumor suppression and immune activation.
By merging novel loading techniques, quantitative analyses (e.g., NanoFCM for precise surface protein copy-number determination), and scalable bioreactor-based production, these state-of-the-art bioengineered exosomes can be rapidly integrated into combination therapies, potentially transforming standard-of-care regimens. Overall, this symposium highlights how innovative exosome engineering from PD-L1 blockade to Trop2 downregulation can reshape the cancer treatment landscape, offering a highly targeted, multifaceted, and immunologically potent approach poised to deliver next-level patient outcomes.