The paper presents the development of a novel lipid-polymer hybrid nanoparticle (NP) platform for drug delivery. The NP is designed to combine the strengths of both polymeric NPs and liposomes, offering high drug encapsulation yield, tunable and sustained drug release, excellent serum stability, and potential for differential targeting. The NP consists of three functional components: a hydrophobic polymeric core for encapsulating poorly water-soluble drugs, a hydrophilic polymeric shell with anti-biofouling properties to enhance stability and circulation half-life, and a lipid monolayer at the interface of the core and shell to promote drug retention and control release. The NP is prepared through a single-step nanoprecipitation method, making it suitable for scale-up. The study demonstrates that the hybrid NP has favorable size, surface charge, drug loading yield, sustained drug release, serum stability, and cellular targeting ability. The NP's ability to encapsulate docetaxel (Dtxl) and release it over 120 hours is highlighted, along with its stability in serum and targeted delivery to prostate cancer cells expressing the PSMA antigen. The platform's simplicity and potential for clinical translation are emphasized.The paper presents the development of a novel lipid-polymer hybrid nanoparticle (NP) platform for drug delivery. The NP is designed to combine the strengths of both polymeric NPs and liposomes, offering high drug encapsulation yield, tunable and sustained drug release, excellent serum stability, and potential for differential targeting. The NP consists of three functional components: a hydrophobic polymeric core for encapsulating poorly water-soluble drugs, a hydrophilic polymeric shell with anti-biofouling properties to enhance stability and circulation half-life, and a lipid monolayer at the interface of the core and shell to promote drug retention and control release. The NP is prepared through a single-step nanoprecipitation method, making it suitable for scale-up. The study demonstrates that the hybrid NP has favorable size, surface charge, drug loading yield, sustained drug release, serum stability, and cellular targeting ability. The NP's ability to encapsulate docetaxel (Dtxl) and release it over 120 hours is highlighted, along with its stability in serum and targeted delivery to prostate cancer cells expressing the PSMA antigen. The platform's simplicity and potential for clinical translation are emphasized.