Endoplasmic reticulum-targeted photodynamic therapy synergizes with rapamycin to induce autophagic cancer cell death

Autophagy plays a dual role in cancer progression, and strategies to drive excessive autophagic flux remain a promising yet challenging therapeutic avenue. Herein, we develop an endoplasmic reticulum (ER)-targeted self-assembling peptide system (P-1-ERT@Rap) that enables localized photodynamic damage and robust ER stress, which synergizes with rapamycin (Rap) for inducing dual autophagy activation in cancer cells. The peptide P-1-ERT co-assembles with Rap into well-dispersed micelles, which exhibit pH-responsive morphological transformation from nanoparticles to nanofibers under acidic conditions, thereby facilitating lysosomal escape and cellular release of therapeutics. Importantly, P-1-ERT selectively accumulates in the ER and generates reactive oxygen species under laser exposure, triggering significant ER stress with upregulation of CHOP proteins. Concurrently, cellular delivery of Rap, an autophagy inducer, further amplifies autophagic flux with increasing LC3B-II/I ratios, ultimately promoting programmed cell death in A375 cells. Notably, the P-1-ERT@Rap system achieves higher tumor accumulation compared to free photosensitizer in vivo. Moreover, intravenous administration of P-1-ERT@Rap alongside laser irradiation significantly inhibits tumor growth in an A375-xenografted mouse model, with minimal systemic toxicity observed. This dual modulation strategy for autophagy regulation effectively enhances photodynamic therapy efficacy, and it offers a promising approach for exploiting organelle specific stress pathways in cancer treatment. STATEMENT OF SIGNIFICANCE: This study presents a endoplasmic reticulum (ER)-targeted self-assembling peptide nanoplatform (P‑1‑ERT@Rap) that integrates organelle-specific photodynamic therapy (PDT) with autophagy modulation for synergistic cancer treatment. The system uniquely exploits pH-responsive morphological transformation from micelles to nanofibers in acidic tumor environments, facilitating lysosomal escape and efficient intracellular delivery. By selectively accumulating in the ER and generating localized reactive oxygen species upon irradiation, it induces severe ER stress and upregulates CHOP, while co-delivered rapamycin further amplifies autophagic flux. This dual activation of autophagy leads to enhanced programmed cell death in melanoma cells, as demonstrated both in vitro and in vivo. Our work provides a pioneering strategy for organelle-precise therapy that leverages dual stress pathways to overcome the limitations of conventional monotherapies. We believe that this new approach has the potential to revolutionize the field of precision oncology, setting a new paradigm for significantly enhancing treatment outcomes across a broad spectrum of tumor types.