Polymeric micelles represent a fundamental self-assembled architecture of gel-based soft materials and have emerged as promising nanocarriers for anticancer drug delivery. Their performance is largely governed by the block composition of constituent copolymers, and understanding their self-assembly behavior provides critical insights into the rational design of gel-related drug delivery systems. In this work, dissipative particle dynamics (DPD) simulations were performed to systematically investigate two types of mixed drug-loaded micellar systems self-assembled from a triblock copolymer mPEG-b-PDEAEMA-b-PMMA (polymer A) with either a diblock copolymer PDEAEMA-b-PMMA (polymer B) or PPEGMA-b-PDEAEMA (polymer C). By tailoring the ratios of hydrophobic (MMA) and pH-sensitive (DMA) blocks, the protonation-responsive behavior, structural stability, drug loading capacity, and release kinetics of the micelles were comprehensively examined. The simulation results demonstrate that: (1) increasing the hydrophobic block ratio accelerates the protonation-triggered micellar swelling and drug release, yet an optimal ratio (+16 MMA) exists beyond which excessive hydrophobic blocks suppress release due to core densification; (2) increasing the pH-sensitive block ratio significantly enhances the maximum drug loading capacity (from 9.83% to 12.22% for the A/C system), but exerts only limited influence on the release rate; (3) the A/C mixed micelles with higher PEG content exhibit superior structural stability and drug loading capacity, while the A/B system with higher MMA content displays more sensitive pH-responsiveness. These findings reveal a competing mechanism between "protonation-driven force" and "structural resistance," providing mesoscopic theoretical guidance for the rational design of pH-responsive gel-related nanocarriers and self-assembled soft materials via block ratio modulation.

Polymeric micelles represent a fundamental self-assembled architecture of gel-based soft materials and have emerged as promising nanocarriers for anticancer drug delivery. Their performance is largely governed by the block composition of constituent copolymers, and understanding their self-assembly behavior provides critical insights into the rational design of gel-related drug delivery systems. In this work, dissipative particle dynamics (DPD) simulations were performed to systematically investigate two types of mixed drug-loaded micellar systems self-assembled from a triblock copolymer mPEG-b-poly(2-(diethylamino)ethyl methacrylate)-b-PMMA (PDEAEMA, hereafter referred to as the DMA block for brevity) with either a diblock copolymer PDEAEMA-b-PMMA (polymer B) or PPEGMA-b-PDEAEMA (polymer C). By tailoring the ratios of hydrophobic (MMA, the constituent block of PMMA) and pH-sensitive (DMA) blocks, the protonation-responsive behavior, structural stability, drug loading capacity, and release kinetics of the micelles were comprehensively examined. The simulation results demonstrate that: (1) increasing the hydrophobic block ratio accelerates the protonation-triggered micellar swelling and drug release because the increased hydrophobic content enhances the core compactness which, upon protonation, generates a stronger driving force for chain extension, yet an optimal ratio (+16 MMA units) exists beyond which excessive hydrophobic blocks suppress release due to core densification; (2) increasing the pH-sensitive block ratio significantly enhances the maximum drug loading capacity (from 9.83% to 12.22% for the A/C system), but exerts only limited influence on the release rate; (3) the A/C mixed micelles with higher PEG content exhibit superior structural stability and drug loading capacity, while the A/B system with higher MMA content displays more sensitive pH-responsiveness. These findings reveal a competing mechanism between “protonation-driven force” and “structural resistance,” providing mesoscopic theoretical guidance for the rational design of pH-responsive polymeric nanocarriers and self-assembled soft materials via block ratio modulation.