Retinoblastoma (RB) represents the most common primary intraocular malignancy in children, driving a critical need for innovative, targeted therapies that enhance tumor control while preserving vision. Current chemotherapy regimens, such as melphalan, can result in significant systemic toxicity and ocular side effects, underscoring the urgency for safer, more selective treatments. Here, we comprehensively report the design and evaluation of a prion-like self-assembling peptide prodrug (Pri-MP) that exploits the elevated macropinocytic uptake in RB cells to deliver an HDMX-targeting peptide, thereby restoring p53 function. Using single-cell RNA sequencing, we identified a key role for Rac1-PAK1 signaling in driving RB-specific macropinocytosis, which facilitated selective intracellular accumulation of Pri-MP through Au(I)-mediated reversible assembly. This strategy enabled potent p53-dependent apoptosis, prompting marked cell cycle arrest and robust tumor suppression . In an orthotopic mouse model, intravitreal Pri-MP significantly curtailed tumor burden and demonstrated the potential for enhanced antitumor activity when combined with melphalan, without imposing systemic toxicity or injuring healthy ocular structures. Mechanistically, Pri-MP antagonizes HDMX, lifting its inhibition of p53 and triggering pro-apoptotic transcriptional programs. By leveraging prion-inspired delivery to achieve high specificity and enhanced safety, this approach addresses a longstanding challenge in RB therapy, where efficient tumor targeting remains paramount and vision preservation is essential. Our findings further confirm the transformative potential of this platform for tumor-specific p53 reactivation, potentially applicable to other neuroectodermal malignancies. Pri-MP thus holds promise as a next-generation modality for eye-preserving RB treatment, meriting further investigation in clinical settings to advance safer, more effective management of this devastating pediatric cancer.