Osteoarthritis (OA) demands localized, on-demand drug delivery due to the limited efficacy of systemic or standard intra-articular therapies, which suffer from rapid clearance and poor targeting. We present a novel stimuli-responsive nanocomposite system comprising amphiphilic core–shell polymer nanoparticles (NPs) embedded in a hydroxypropyl methylcellulose-C₁₂ (HPMC-C₁₂) hydrogel matrix. Crucially, the NPs are produced via a microfluidic chip process, yielding highly uniform sizes with polydispersity index (PDI) < 0.1. This microfluidic approach overcomes the drastic polydispersity and batch-to-batch inconsistencies of conventional nanoparticle synthesis, ensuring reproducible NP characteristics and enhanced drug loading capacity. The NP polymer architecture has been rationally tuned for pH-responsiveness: it remains stable at physiological pH, yet rapidly triggers payload release at pH 6.5, mimicking the acidic microenvironment of inflamed OA joints. This precise pH-triggered behavior targets drug release to diseased tissue while minimizing off-target leakage. In vitro studies of the NP–hydrogel composite in buffered media demonstrated sharply differential release profiles: at pH 7.4 the composite showed negligible drug release, whereas at pH 6.5 it achieved sustained release of encapsulated payloads over days. Notably, the hydrogel’s porous network allows for co-loading of large biologics, while the NP cores carry hydrophobic small-molecule drugs. Using doxorubicin as a model drug and relevant OA therapeutic candidates, we confirm that the system can concurrently deliver a small molecule and a high-molecular-weight protein with distinct release kinetics. Such dual delivery leverages the hydrogel for slow protein release and the NPs for controlled small-drug release, addressing the need for combination therapy in OA. Co-delivery of small and macromolecular therapeutics is increasingly recognized for synergistic treatment efficacy, and our composite provides a single injectable platform to achieve this. Preliminary in vivo evaluations in rat OA models indicate excellent biocompatibility and localization of the composite, with ongoing studies to quantify its therapeutic impact.