A novel lipid-polymer hybrid nanoparticle (NP) platform was developed for efficient drug delivery. This hybrid NP consists of a hydrophobic polymeric core for drug encapsulation, a hydrophilic polymeric shell to enhance stability and circulation time, and a lipid monolayer at the interface to improve drug retention. The NP is synthesized via a single-step nanoprecipitation method, ensuring reproducibility and scalability. The hybrid NP offers high drug encapsulation efficiency, tunable and sustained drug release, and excellent serum stability. It also enables targeted delivery to specific cells or tissues. The NP is composed of three distinct components: a biodegradable hydrophobic polymeric core that can carry poorly water-soluble drugs, a stealth hydrophilic shell that prevents immune recognition and increases circulation time, and a lipid monolayer that prevents drug leakage and reduces water penetration. The NP is prepared using ester-terminated poly(D,L-lactic-co-glycolic acid) (PLGA) as the hydrophobic core, polyethylene glycol (PEG) conjugated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophilic shell, and lecithin as the lipid monolayer. The NP is self-assembled through a single-step nanoprecipitation method, resulting in sub-100 nm particles with favorable size and zeta potential for drug delivery. The hybrid NP demonstrated superior drug encapsulation and sustained release compared to PLGA-PEG and PLGA NPs. The lipid monolayer at the interface of the core and shell acts as a molecular fence, enhancing drug retention and release control. The NP also showed excellent serum stability, with minimal size increase in 10% BSA or plasma solutions. The NP was further functionalized with A10 RNA aptamers for targeted delivery to prostate-specific membrane antigen (PSMA)-expressing cells, demonstrating selective uptake by LNCaP cells over PC3 cells. The hybrid NP platform combines the advantages of polymeric NPs and liposomes, offering a robust and versatile drug delivery system with potential for clinical translation. The NP's simple synthesis process and tunable properties make it suitable for large-scale production and further in vivo evaluation.A novel lipid-polymer hybrid nanoparticle (NP) platform was developed for efficient drug delivery. This hybrid NP consists of a hydrophobic polymeric core for drug encapsulation, a hydrophilic polymeric shell to enhance stability and circulation time, and a lipid monolayer at the interface to improve drug retention. The NP is synthesized via a single-step nanoprecipitation method, ensuring reproducibility and scalability. The hybrid NP offers high drug encapsulation efficiency, tunable and sustained drug release, and excellent serum stability. It also enables targeted delivery to specific cells or tissues. The NP is composed of three distinct components: a biodegradable hydrophobic polymeric core that can carry poorly water-soluble drugs, a stealth hydrophilic shell that prevents immune recognition and increases circulation time, and a lipid monolayer that prevents drug leakage and reduces water penetration. The NP is prepared using ester-terminated poly(D,L-lactic-co-glycolic acid) (PLGA) as the hydrophobic core, polyethylene glycol (PEG) conjugated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophilic shell, and lecithin as the lipid monolayer. The NP is self-assembled through a single-step nanoprecipitation method, resulting in sub-100 nm particles with favorable size and zeta potential for drug delivery. The hybrid NP demonstrated superior drug encapsulation and sustained release compared to PLGA-PEG and PLGA NPs. The lipid monolayer at the interface of the core and shell acts as a molecular fence, enhancing drug retention and release control. The NP also showed excellent serum stability, with minimal size increase in 10% BSA or plasma solutions. The NP was further functionalized with A10 RNA aptamers for targeted delivery to prostate-specific membrane antigen (PSMA)-expressing cells, demonstrating selective uptake by LNCaP cells over PC3 cells. The hybrid NP platform combines the advantages of polymeric NPs and liposomes, offering a robust and versatile drug delivery system with potential for clinical translation. The NP's simple synthesis process and tunable properties make it suitable for large-scale production and further in vivo evaluation.