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Medication in arthritis therapies is complex because the inflammatory progression of rheumatoid arthritis (RA) and osteoarthritis (OA) is intertwined and influenced by one another. To address this problem, drug delivery systems (DDS) are composed of four independent exogenous triggers and four dependent endogenous stimuli that are controlled on program and induced on demand, respectively. However, the relationships between the mechanisms of endogenous stimuli and exogenous triggers with pathological alterations remain unclear, which results in a major obstacle in terms of clinical translation. Thus, the rationale for designing a guidance system for these mechanisms via their key irritant biosensors is in high demand. Many approaches have been applied, although successful clinical translations are still rare. Through this review, the status quo in historical development is highlighted in order to discuss the unsolved clinical difficulties such as infiltration, efficacy, drug clearance, and target localisation. Herein, we summarise and discuss the rational compositions of exogenous triggers and endogenous stimuli for programmable therapy. This advanced active pharmaceutical ingredient (API) implanted dose allows for several releases by remote controls for endogenous stimuli during lesion infections. This solves the multiple implantation and local toxic accumulation problems by using these flexible desired releases at the specified sites for arthritis therapies.