<p>Targeted therapy enhances tumor elimination while reducing adverse effects by integrating multiple tumoricidal mechanisms. Low molecular weight (LMW) ligands, offering faster pharmacokinetics and improved tumor permeability, present a viable alternative to antibodies. This study presents a novel nanomedicine for prostate cancer therapy, leveraging mesoporous silica nanoparticles (MSN) as the nanocarrier to encapsulate manganese dioxide (MnO₂) and doxorubicin (DOX). The resultant nanoparticles are further coated with a polydopamine (PDA) layer and covalently conjugated with glucose oxidase (GOx), forming the MSN@Mn@PDA-GOx/DOX hybrid system (hereafter termed SMPG/DOX NPs). LMW ligands (small-molecule inhibitor DCL and nanobody VHH) targeting prostate-specific membrane antigen (PSMA) were conjugated to create DCL-SMPG/DOX and VHH-SMPG/DOX. Mn²⁺-mediated Fenton-like reactions converted H₂O₂ into toxic hydroxyl radicals (·OH) under acidic conditions, enabling chemodynamic therapy (CDT). GOx-generated H₂O₂ and gluconic acid disrupted nutrient supply, inducing tumor starvation therapy (ST). The increased H₂O₂ and acidity amplified the Fenton-like reaction, creating a "ROS storm" that synergistically enhanced chemotherapy. LMW targeting improved tumor specificity, efficacy, and reduced side effects. In vitro, DCL-SMPG/DOX showed superior tumor cell internalization and cytotoxicity compared to VHH-SMPG/DOX. In vitro, the cellular internalization rates of VHH-SMPG/DOX and DCL-SMPG/DOX were 34.1% and 44.5%, respectively, significantly higher than that of free DOX uptake (10.3%). Moreover, DCL-SMPG/DOX-induced stronger cytotoxicity compared to VHH-SMPG/DOX. In vivo studies further demonstrated the strong anti-tumor activity of the DCL-SMPG/DOX nanomedicine, underscoring its potential as a prostate cancer treatment. Further research is needed to elucidate its anti-tumor mechanisms. </p>