Owing to their attractive physicochemical and morphological attributes, mesoporous silica nanoparticles (MSNs) have attracted increasing attention over the past two decades for their utilization in diversified fields. Despite the success, these highly stable siliceous frameworks often suffer from several shortcomings of compatibility issues, uncontrollable degradability leading to long-term retention , and substantial unpredictable toxicity risks, as well as deprived drug encapsulation efficiency, which could limit their applicability in medicine. Along this line, various advancements have been made in re-engineering the stable siliceous frameworks, such as the incorporation of diverse molecular organic, as well as inorganic (cationic and anionic) species and monitoring the processing, as well as formulation parameters, resulting in the hetero-nanostructures of irregular-shaped (Janus and multi-podal) and dynamically-modulated (deformable solids) architectures with high morphological complexity. Insightfully, this review gives a brief emphasis on re-engineering such stable siliceous frameworks through modifying their intrinsic structural and physicochemical attributes. In conclusion, we recapitulate the review with exciting perspectives.