Despite significant advances in antisense oligonucleotide (ASO) chemistry and nanocarrier design, therapeutic efficacy is often limited by inefficient cellular uptake and sequestration within endosomal–lysosomal compartments. Here, we show that ionizing radiation can be leveraged to overcome these barriers and enhance antisense nanomedicine delivery in castration-resistant prostate cancer (CRPC). CRPC cells (PC-3, C4-2) exhibited greater resistance to irradiation than castration-sensitive prostate cancer cells (LNCaP) and upregulated heat shock protein 27 (HSP27) in response to radiation, indicating an adaptive stress response. HSP27 downregulation by HSP27 mRNA -targeting ASO restored radiation-induced apoptotic signaling. To improve intracellular delivery, we developed lipid-modified ASOs (LASOs) targeting HSP27 mRNA that self-assemble into nanomicelles and enter cells via macropinocytosis. Although LASOs showed enhanced cellular uptake, they were predominantly sequestered within endosome–lysosome compartments, limiting their therapeutic activity. Strikingly, irradiation promoted endosomal-lysosomal escape of LASO nanomicelles, facilitating cytoplasmic delivery, robust HSP27 suppression, ultimately leading to increased anti-cancer effects, including an approximately 75% reduction in CRPC cell viability and delayed CRPC 3D spheroid growth. Collectively, these findings reveal a bidirectional therapeutic synergy in which HSP27 silencing resensitizes CRPC cells to radiation while irradiation enhances LASO intracellular trafficking. This study establishes irradiation as a trigger for intracellular drug release and provides a synergistic strategy integrating radiotherapy with antisense nanomedicine to overcome delivery barriers and restore therapeutic efficacy in CRPC.

Introduction: Lobectomy with lymph node dissection is the gold standard treatment for stage IA–IIA Non-Small Cell Lung Cancer (NSCLC). Surgery is responsible for higher early mortality but offers better overall long-term survival. The patient population concerned is often elderly and combines the comorbidities of smoking and age. Several trials have shown good results of stereotactic radiotherapy (SABR) in terms of local control and tolerance in elderly subjects. Our objective is to study the survival and regional control of patients over 75 years treated by surgery or SABR for localized NSCLC. Materials and Method: We conducted a single-center retrospective study between January 2012 and December 2022 including elderly patients who received surgery or SABR for NSCLC less than 5 cm in size, N0, M0. A cumulative comorbidity index was calculated for each patient, considering severity and impact of treatment. We performed subgroup analyses using CART method to identify factors impacting survival and early death. Results: After propensity score matching, 127 operated patients were matched to 85 patients treated with SABR. Overall survival at 1 and 5 years for the operated patients was 83.87% and 47.30% compared with 88.8% and 31.5% in the radiotherapy group (p = 0.068). We have identified four factors influencing the incidence of early mortality: gender, World Health Organization Performance status (WHO status), Forced Expiratory Volume in 1 s (FEV1), and treatment group. Conclusions: Surgery seems to remain the standard of treatment in terms of overall survival and locoregional recurrence, in a context where SABR nevertheless provides excellent local control and tolerance in the short and long term. In order to improve patient selection, we are proposing for the first time a tool to aid therapeutic decision-making.