Implantable tissue engineering scaffolds with temporally programmable multi-drug release are recognized as promising tools to improve therapeutic effects. A good example would be one that exhibits initial anti-inflammatory and long-term anti-tumor activities after tumor resection. In this study, a new strategy for self-coated interfacial layer on drug-loaded mesoporous silica nanoparticles (MSNs) based on mussel-mimetic catecholamine polymer (polydopamine, PDA) layer was developed between inorganic and organic matrix for controlling drug release. When the interface PDA coated MSNs were encapsulated in electrospun poly(L-lactide) (PLLA) fibers, the release rates of drugs located inside/outside the interfacial layer could be finely controlled, with short-term release of anti-inflammation ibuprofen (IBU) for 30 days in absence of interfacial interactions and sustained long-term release of doxorubicin (DOX) for 90 days in presence of interfacial interactions to inhibit potential tumor recurrence. The DOX@MSN-PDA/IBU/PLLA hybrid fibrous scaffolds were further found to inhibit proliferation of inflammatory macrophages and cancerous HeLa cells, while supporting the normal stromal fibroblast adhesion and proliferation at different release stages. These results have suggested that the interfacial obstruction layer at the organic/inorganic phase was able to control the release of drugs inside (slow)/outside (rapid) the interfacial layer in a programmable manner. We believe such interface polymer strategy will find applications in where temporally controlled multi-drug delivery is needed. (C) 2015 Elsevier B.V. All rights reserved.