Core-shell conjugated polymer nanoparticles (CPNs) were fabricated by complexing a semi-flexible, primary amine-containing conjugated polymer (CP) with hyaluronic acid (HA). Flexibility introduced in the rigid rod conjugated backbone allows backbone reorganization to increase π-π interaction under ionic complexation, resulting in core-shell nanoparticles with a hydrophobic CP core wrapped with a HA shell. The core-shell nanoparticles exhibited no cellular toxicity and high cancer cell specificity with minimal binding to normal cells.