Porosity-engineered long-acting protopanaxadiol microspheres prevent CDK4/6 inhibitor-induced myelosuppression.

CDK4/6 inhibitor-induced myelosuppression frequently necessitates treatment interruption or dose reduction, yet effective pharmacological interventions specifically addressing this persistent hematological toxicity remain limited. Here, we report a porosity-programmed protopanaxadiol-loaded PLGA microsphere (PPD-MS) system for rapid-onset and long-acting myeloprotection during anticancer treatment. Using a continuous-flow O/W microsphere fabrication strategy, microsphere porosity and core-shell architecture were precisely regulated by tuning aqueous-phase osmotic pressure, establishing a controllable process-structure-release relationship. The optimized PPD-MS rapidly achieved a stable plasma plateau within 0.5 h after intramuscular injection and maintained sustained systemic exposure for 19 days, with a strong in vitro-in vivo correlation between release profiles (R2 = 0.9983). Their narrow particle-size distribution enabled smooth administration through a 26G needle, supporting clinical feasibility. In chemotherapy- and CDK4/6 inhibitor-induced myelosuppression models, PPD-MS effectively restored peripheral blood cell counts, bone marrow cellularity, and hematopoietic stem and multipotent progenitor populations. Mechanistically, PPD-MS rescued hematopoietic cell-cycle progression by activating PI3K/AKT signaling, suppressing p21-mediated inhibition, and restoring the Rb/E2F1-Cyclin E/CDK2 axis, thereby reversing CDK4/6 inhibitor-induced G1/S arrest. Moreover, combination treatment with paclitaxel or CDK4/6 inhibition enhanced antitumor efficacy, accompanied by increased cytotoxic immune activation and reduced PD-L1-associated immune escape. Collectively, this study establishes a porosity-engineered long-acting microsphere platform that integrates predictable drug release, rapid and sustained myeloprotection, and improved combination anticancer therapy, providing a translational strategy for managing CDK4/6 inhibitor-associated hematological toxicity.