Embedding Diselenide Cross‐Linked Polymer Nanoparticles In Situ Using Ring‐Opening Metathesis Polymerization (ROMP) of NORBORNENE Derived Block Copolymers for ROS‐Responsive Doxorubicin (DOX) Drug Delivery

We developed diselenide‐crosslinked polymeric nanoparticles using a ROMP‐synthesized amphiphilic block copolymer, PNEG‐b‐(Nor‐SeH). The selenol group was introduced via nucleophilic substitution of sodium diselenide with PNEG‐b‐(Nor‐Cl), followed by self‐assembly into PNPs via oxidative crosslinking, forming an ROS‐sensitive linker. 1 H NMR study confirmed the successful synthesis of monomer and polymer (PNEG‐ b ‐(Nor‐Cl)). GPC analysis confirmed the successful synthesis of block copolymer (Mn = 79.9 kDa). EDS analysis of DC PNPs showed a selenium content of ~8.02 wt%, confirming successful Se incorporation. The DLS analysis revealed that blank DC PNPs are at 190 ± 5.3 nm and enlarge slightly to 207 ± 8.9 nm after DOX loading, which is suitable for EPR‐mediated tumor accumulation. The diselenide shell endowed PNPs with strong colloidal stability, holding their size essentially constant for 72 h of studies in normal conditions with the least DOX release rate (~10%). In contrast, ROS challenge triggered rapid liberation of drug: at 10 μM H 2 O 2 (52%) was released and ~93% at 50 μM H 2 O 2 within the same window of 72 h, confirming efficient, tumor‐relevant responsiveness. MTT assay showed cytotoxic effects on HeLa cells, with viability decreasing to 35% at higher DOX@DC PNPs concentrations, while normal cells maintained 92% viability. Cellular uptake analysis showed doubled intracellular fluorescence after 12 h.