Precision targeting of ALK-positive lung cancer: Engineering HFN@MS4078 nanocages for optimized PROTAC delivery

Protein hydrolysis-targeted chimeras (PROTACs) are heterobifunctional molecules designed for the selective degradation of target proteins. MS4078, a novel PROTAC, shows promise for treating ALK-positive non-small cell lung Cancer (NSCLC), yet its clinical efficacy is hindered by suboptimal tumor targeting and off-target toxicities. To enhance its therapeutic profile, we developed human heavy chain ferritin (HFN) as a targeted delivery system, leading to the creation of HFN@MS4078 nanocages. Prepared via passive loading, HFN@MS4078 achieved a drug loading capacity of 178 molecules per nanocage with a HFN recovery rate of 70.1 %. The nanocages exhibited a rapid release profile under lysosomal conditions (pH 5.0), with approximately 80 % drug release after 60 h, while maintaining over 80 % stability at physiological pH 7.4. In vitro, HFN@MS4078 was actively internalized into lysosomes via TfR1 receptor binding, resulting in a 2.7-2.8 times reduction in IC₅₀ values compared to free MS4078. Furthermore, HFN@MS4078 significantly decreased the expression levels of ALK, p-ALK, p-AKT, and p-ERK in NCI-H2228 and NCI-H3122 cell lines. In vivo, HFN@MS4078 substantially reduced tumor volume and prolonged survival while exhibiting negligible systemic toxicity. These results suggest that HFN@MS4078 represents a promising strategy for targeted therapy in ALK-positive NSCLC, enhancing therapeutic efficacy while minimizing systemic toxicity.