Emerging therapies for lung adenocarcinoma: Mechanistic and efficacy insights from spheroid-based <i>in vitro</i> models

The persistent challenges of drug resistance, tumor heterogeneity, and poor predictability of traditional 2D and animal models underscore the urgent need for innovative strategies in development of safe and efficacious anti-cancer interventions. In recent years, novel drug delivery systems (NDDS) such as nanoparticles, liposomes, antibody-drug conjugates, as well as inhalable formulations have emerged as promising approaches to enhance drug targeting, efficacy, and safety, particularly in hard-to-treat malignancies like lung cancer. Concurrently, 3D in vitro tumor spheroid models have gained recognition for their ability to recapitulate key features of the tumor microenvironment, including cell-cell and cell-matrix interactions, oxygen gradients, and drug penetration barriers. This manuscript presents a comprehensive compilation of the NDDS that have been evaluated using spheroid models and demonstrated substantial therapeutic potential, with many demonstrating translational success in subsequent animal studies. By highlighting the correlation between spheroid-based screening outcomes and in vivo efficacy, we aim to highlight the importance of spheroid models as efficient, reproducible, and ethically favorable tools for early-phase drug evaluation. Overall, this review emphasizes the dual relevance of NDDS and in vitro spheroid systems in advancing precision oncology while promoting the reduction of animal usage in research.