The drug as its own reporter: unveiling doxorubicin's intrinsic CEST signal for self-reporting release.

Current approaches for visualizing drug release rely on exogenous contrast agents, which face regulatory hurdles and may alter drug pharmacokinetics. Here, we discover that doxorubicin (DOX) itself possesses intrinsic chemical exchange saturation transfer (CEST) properties-a functionality overlooked for decades. To exploit this finding, we rationally design a self-reporting nanoplatform (DOX@MSNs-PLO) by conjugating the cationic membrane-lytic polypeptide poly(L-ornithine) (PLO) onto mesoporous silica nanoparticles (MSNs) and loading DOX into the mesopores. Material characterization reveals that spatial confinement within the MSN mesopores restricts the CEST-active molecular dynamics of DOX, completely silencing the CEST signal; upon release, the signal is quantitatively restored. This structure-dependent on-off switch enables label-free, real-time monitoring of drug release. Furthermore, the PLO-functionalized surface imparts potent membrane-lytic activity, synergizing with DOX to overcome drug resistance. Across sensitive and DOX-resistant breast cancer cells, DOX@MSNs-PLO exhibits potent synergy (combination index <1). By unveiling the hidden CEST dimension of a conventional chemotherapeutic and integrating it into a rationally designed MSN architecture, this work establishes a materials chemistry paradigm wherein the drug serves as its own reporter, seamlessly merging therapy and tracking.