A clinically inspired olsalazine-based metal-organic framework enables a universal nanodrugs platform for diverse disease.

Conventional nanocarriers have three inherent limitations: therapeutic inefficacy, suboptimal drug-loading capacity, and disease-specific nanocarrier requirements necessitating frequent structural reconfiguration. To overcome these challenges, we developed a novel modular synergistic bioactive nanocarrier based on olsalazine (Olsa), utilizing a modular coordination-switching strategy to achieve cross-disease therapeutic adaptability. A spherical Olsa-based Cu/Fe metal-organic framework (MOF) was developed for colorectal cancer (CRC) therapy to encapsulate doxorubicin (DOX) and address the intrinsic hydrogen peroxide (HO) deficiency in tumor microenvironments through a self-catalytic HO regeneration mechanism. This approach exhibited a 2.3 ± 0.1-fold enhancement in tumor-selective cytotoxicity and a 10.6 ± 2.2-fold enhancement in tumor accumulation efficiency. The synergistic combination of photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and immunotherapy creates a self-reinforcing therapeutic cascade that concurrently mitigates therapy-induced inflammatory responses and enhances immunogenic cell death (ICD) through damage-associated molecular patterns (DAMP) activation. A biconical Ce-Olsa MOF oral nanotherapeutic was developed for ulcerative colitis (UC) management, serving as a dual-function nanocarrier that simultaneously scavenges pathogenic reactive oxygen species (ROS) and facilitates ROS-mediated mesalazine release. This spatiotemporally controlled release profile resulted in significant downregulation of pro-inflammatory cytokines and complete restoration of tight junction protein expression. This study pioneers a transformative nanocarrier that revolutionizes therapeutic nanocarrier design through three innovations: (i) the synergistic integration of therapeutic and nanocarrier functionalities using intrinsically bioactive molecules, (ii) universal disease adaptability for precision intervention across multiple pathological conditions through modular coordination switching, and (iii) clinically validated, Food and Drug Administration (FDA)-approved molecules with proven biocompatibility.