Drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic chemotherapy decreases the extent of drug-free periods, thereby hindering the development of drug resistance. Intraperitoneal chemotherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemotherapy remains difficult. We hypothesized that modulating the surface properties of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic localized chemotherapy in vivo. Chemotherapeutic drugs were encapsulated in particles coated with a layer of polydopamine and a subsequent layer of polyethylene glycol (PEG). These particles achieved a 3.8-fold higher loading content compared to nanoparticles formulated from traditional linear PLGA-PEG co-polymers. In vitro release kinetic studies and in vivo drug distribution profiles demonstrate sustained drug release. Whereas free drug conferred no survival advantage, low-dose intraperitoneal administration of drug-laden, surface-coated nanoparticles to mice bearing drug-resistant ovarian tumors resulted in significant survival benefits in the absence of any apparent systemic toxicity. We have additionally investigated the possibility of conjugating biologics to the surface of these biodegradable particles to concentrate these molecules at the desired site of action. Excitingly, it was observed that such immobilization can enhance the activity of enzymes in vivo.