Acid‐Responsive Disassembly of Nanomedicines for Extracellular Drug Delivery Reversing Glioblastoma Immunosuppressive Microenvironment by Targeting the Adenosine‐A2AR Pathway

Abstract The efficacy of checkpoint blockade immunotherapy for glioblastoma (GBM) is significantly influenced by the precise delivery of therapeutic agents that can penetrate the blood‐brain barrier (BBB) and reprogram the tumor immune microenvironment. Conventional nanoscale carriers used for delivering immune checkpoint blockers are more likely to be internalized by tumor cells, leading to a loss of drug efficacy. This study presents a phosphatidylcholine (PC)‐coated nanoparticle (PCNP) with an optimized PC ratio on its surface, achieving a balanced surface charge. This surface optimization minimizes nanoparticle‐cell membrane interactions, reducing cellular uptake and thereby enhancing extracellular drug targeting efficacy. The constructed PC shell enabled PCNPs to penetrate the BBB mediated by choline transporters. The PC shell can attenuate interactions between PCNPs and cells, thereby preventing the internalization of PCNPs. Additionally, the poly‐ l ‐histidine core can undergo protonation in the acidic microenvironment, resulting in rapid disintegration of PCNPs and facilitating the quick release of the encapsulated CPI‐444 (an extracellular adenosine receptor blocker) and temozolomide, inducing immunogenic cell death and blocking extracellular adenosine receptors to reverse the immunosuppressive feedback signaling pathway of the adenosinergic axis. This combination therapy has shown a novel therapeutic strategy for extracellular immune checkpoint blockade in GBM.