Biocompatible nano-to-microscale particles offer significant advantages for therapeutic applications, particularly in targeted and sustained drug delivery for lung diseases such as chronic obstructive pulmonary disease (COPD). This study focuses on the fabrication of porous core–shell microparticles encapsulating bioactive telodendrimer (TD) nanodrug carriers using electrospray technology. The microparticles were designed to enhance pulmonary drug delivery by optimizing particle size (1–5 μm) and morphology for deep lung deposition and controlled drug release. The effects of solution viscosity and surface tension on microparticle formation were systematically investigated. Results demonstrated that higher polymer concentration and controlled electrospray parameters yielded spherical microparticles with uniform porosity, essential for sustained drug release. Surfactant addition reduced particle size and enhanced pore formation but introduced challenges such as morphological variability. In vitro cytotoxicity, hemolysis, and drug release studies confirmed the biocompatibility and therapeutic potential of the fabricated microparticles. The findings highlight the promise of electrospray-derived core–shell microparticles for non-invasive COPD treatment, warranting further exploration into polymer-solvent interactions and formulation refinements for optimized drug delivery.