In this study, we employ mechanochemistry as an innovative strategy, using a Planetary Mill, to obtain supramolecular structures in the solid state between Curcumin (Cur) and β‐cyclodextrin (βCD), exploring different parameters such as jars and balls material (stainless steel versus zirconium oxide), milling time, as well as the effect on imposing different Cur:βCD molar ratios. Our findings demonstrate that regardless of the milling material used, the same supramolecular interactions between Cur and βCD seem to be promoted. However, depending on the molar ratio, different supramolecular modes are produced resulting in inclusion complexes (ICs) or non‐inclusion complexes (non‐ICs) by a partial or total amorphization of both Cur and βCD. Independently of the type of supramolecular complex obtained (ICs/or non‐ICs), high content of Cur was quantified in all the systems, achieving a Cur content of up to 342 mg per mmol of βCD, along with an enhancement in Cur aqueous solubility. The Cur:βCD 1 : 2 complex showed the highest aqueous solubility (around 10‐times more soluble than milled Cur). In our conditions, the optimum time to form the supramolecular complexes was 60 min. The stability of the complexes was directly related to the extent of encapsulation of Cur inside the βCD cavity.

Since its conceptualization, click chemistry in all its variants has proven to be a superior synthesis protocol, compared to conventional methods, for forming new covalent bonds under mild conditions, orthogonally, and with high yields. If a term like reactive resilience could be established, click reactions would be good examples, as they perform better under increasingly challenging conditions. Particularly, highly hindered couplings that perform poorly with conventional chemistry protocols—such as those used to conjugate biomacromolecules (e.g., proteins and aptamers) or multiple drugs onto macromolecular platforms—can be more easily achieved using click chemistry principles, while also promoting high stereoselectivity in the products. In this review, three molecular platforms relevant in the field of nanomedicine are considered: polymers/copolymers, cyclodextrins, and fullerenes, whose functionalization poses a challenge due to steric hindrance, either from the intrinsic bulk behavior (as in polymers) or from the proximity of confined reactive sites, as seen in cyclodextrins and fullerenes. Their functionalization with biologically active groups (drugs or biomolecules), primarily through copper-catalyzed azide–alkyne cycloaddition (CuAAC), strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron-demand Diels–Alder (IEDDA) and thiol–ene click reactions, has led to the development of increasingly sophisticated systems with enhanced specificity, multifunctionality, bioavailability, delayed clearance, multi-targeting, selective cytotoxicity, and tracking capabilities—all essential in the field of nanomedicine.