An Abraxane-based albumin nanoplatform loaded with a STING agonist for synergistic dual immunotherapy of triple-negative breast cancer.

Abraxane has been a frequently used frontline chemotherapeutic drug for clinically treating several advanced cancers, including non-small cell lung cancer (NSCLC), pancreatic cancer, and triple-negative breast cancer (TNBC), however, the therapeutic efficiency of Abraxane for tumor immunotherapy that largely relies on the immunogenic cell death (ICD) of paclitaxel (PTX) remains quite limited and thus requires significant improvements. Development of an Abraxane-based albumin nanoplatform for simultaneous loading of a STING agonist is a straightforward yet efficient means to achieve synergistic dual immunotherapy with maintained translatable potentials. For this purpose, we report herein the leverage of Human Serum Albumin (HSA) for simultaneous loading of PTX and an oral small-molecule STING agonist, MSA-2 with an optimized combinatory index (CI) via the Nab™ technology of Abraxane without the use of any exogenous excipients to overcome the low efficiency of PTX for antigen presentation and compromised oral targeting properties of MSA-2, affording an Abraxane-based albumin nanoplatform, PTX/MSA-2@HSA, PMH NPs with high drug-loading contents (DLCs). Stabilized PMH NPs with a mean hydrodynamic diameter of 140.1 nm can target tumors via both the enhanced permeation and retention effect (EPR) effect and Gp60-mediated endocytosis, and more importantly, synergistically activate the STING-mediated innate immunity and ICD-induced adaptive immunity, leading to a high tumor growth inhibition (TGI) of 87.1% in a Balb/c murine TNBC model. Notably, PMH NPs induce long-term immune memory with a maturation rate of memory T cells as high as 15.7%. Overall, this study not only provides a straightforward yet robust means for the safe delivery of small-molecule STING agonists for combined immunotherapy, but also offers new insights into the translation of nanodrugs from preclinical research to clinical application.