It takes Two: Advancing cancer treatment with two-step nanoparticle delivery

The rapid advancement of nanobiotechnology has resulted in the development of numerous targeted nanoformulations and sophisticated nanobiorobots for biomedical applications. Despite the potential of nanostructures to improve drug delivery and therapeutic efficacy, their clinical application is still constrained by insufficient accumulation in tumor tissues. Current methodologies result in only an average of 0.6 % of administered nanoparticles reaching tumors, prompting the development of innovative strategies to improve targeting and influence the pharmacokinetics and pharmacodynamics of drugs. One such approach is two-step targeting, which includes either the concept of tumor pre-targeting with specific recognizing elements or the stimuli-sensitive activation of nanostructures. This review critically evaluates advancements in two-step drug delivery systems utilizing nanobiotechnology for targeted cancer therapy. For instance, two-step delivery based on the pre-targeting concept involves an initial injection of targeting molecules that bind to tumor-specific antigens, followed by the administration of drug-loaded nanocarriers modified with complementary adaptors. This approach enhances nanoparticle accumulation in tumors and improves therapeutic outcomes by increasing interaction avidity and overcoming steric hindrances. We critically assess existing adaptor systems for two-step drug delivery and synthesize findings from various studies demonstrating their efficacy in both in vitro and in vivo settings, while addressing challenges in clinical translation. We also explore future directions for developing novel adaptor systems to enhance two-step delivery mechanisms. This review aims to contribute to optimizing nanobiotechnology in oncology for more effective cancer therapies.