Nanobodies targeting the tumor microenvironment and their formulation as nanomedicines

Among the emerging strategies for cancer theranostics, nanomedicines offer significant promise in advancing both patients’ diagnosis and treatment. In combination with nanobodies, nanomedicines can potentially enhance the precision and efficiency of drug or imaging agent delivery, addressing key limitations of current approaches, such as off-target toxicities. The development of nanomedicines will be further accelerated by the creation of smart nanoparticles, and their integration with immunotherapy. Obviously, the success of nano-immunotherapy will depend on a comprehensive understanding of the tumor microenvironment, including the complex interplay of mechanisms that drive cancer-mediated immunosuppression and immune escape. Hence, effective therapeutic targeting of the tumor microenvironment requires modulation of immune cell function, overcoming resistance mechanisms associated with stromal components or the extracellular matrix, and/or direct elimination of cancer cells. Identifying key molecules involved in cancer progression and drug resistance is, therefore, essential for developing effective therapies and diagnostic tools that can predict patient responses to treatment and monitor therapeutic outcomes. Current nanomedicines are being designed with careful consideration of factors such as the choice of carrier (e.g., biocompatibility, controlled cargo release) and targeting moiety. The unique properties of nanobodies make them an effective engineering tool to target biological molecules with high affinity and specificity. In this review, we focus on the latest applications of nanobodies for targeting various components of the tumor microenvironment for diagnostic and therapeutic purposes. We also explore the main types of nanoparticles used as a carrier for cancer immunotherapies, as well as the strategies for formulating nanoparticle-nanobody conjugates. Finally, we highlight how nanobody-nanoparticle formulations can enhance current nanomedicines.