Engineering an advanced multicomponent pentacyclic triterpenoid nanoplatform for synergistic co-delivery of cyclin-dependent kinase 4/6 inhibitors to enhance cancer chemoimmunotherapy.

Immune checkpoint inhibitors such as monoclonal antibodies anti-PD-L1 hold huge promise for triple-negative breast cancer (TNBC) therapy but face limited immune efficacy due to the cold tumor nature and suppressive tumor immune microenvironment (TIME). To address these challenges, we engineered an innovative multi-component natural triterpenoid (PT)-co-assembled nano-platform that simultaneously serves as immunogenic cell death (ICD)-inducing chemotherapeutics for synergistic delivery of palbociclib (Pal), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor with distinct immunomodulatory effects but lacking effective synergistic agents. By systematically screening four PT molecules, we identified that all binary PT systems could effectively regulate Pal delivery behavior. Analysis of representative nano-OMPal, composed of oleanolic acid (OA), maslinic acid (MA), and Pal, revealed that π-π stacking, hydrogen bonding, and hydrophobic interactions among its components are key driving forces behind successful co-assembly. Importantly, the combination of OA and MA not only enhances apoptotic and necrotic effects but also amplifies Pal-induced G1/S phase arrest by strongly suppressing key cell cycle regulators. Moreover, the as-prepared nano-assemblies exhibit multiple therapeutic benefits and cumulative ICD induction, synergistically activating anti-PD-L1 immune responses and effectively reversing the TIME. This study highlights the potential of natural product-based multi-component nanoplatforms as a transformative strategy for integrating ICD induction, chemotherapy, and immunotherapy, offering a potential avenue to address CDK4/6 inhibitor deficiencies and advance TNBC precision therapy.