Cancer is thus far one of the most challenging diseases, which has negatively affected the life expectancy and quality of human beings [1]. Among various therapeutic modalities, chemotherapy remains the most common strategy for cancer treatments in clinical practice [2], [3], [4]. Although great efforts have been made in the past decades to improve the targeting efficiency and systemic circulation for chemotherapeutic agents [5,6], several significant challenges of chemotherapy, such as drug resistance and side effects, still remain [7]. Co-delivery of two or more therapeutic agents to achieve dual- or multi-modality combination therapy has been recognized as one of the most effective strategies to improve the therapeutic outcome of cancer chemotherapy, because they often exhibit synergistic effects with reduced dosages and side effects of chemotherapeutic agents, when compared with single treatment modality [8], [9], [10]. Moreover, the recent booming of nano drug delivery systems has made possible to simultaneously integrate various therapeutic agents into one nanomedicine for achieving synergistic effect [11]. For instance, Wang and coworkers [12] reported the co-loading of 10-hydroxycamptothecin and doxorubicin into a hollow zeolitic imidazolate framework (ZIF) nanostructure for combination cancer therapy. The dual-drug treatment exhibited a near four-fold improvement in the tumor inhibition rate, when compared with the single drug-based treatment. Furthermore, Sun and coworkers [13] reported the conjugation of a hypoxia-activated prodrug with a photosensitizer, which self-assembled into nanoparticles to achieve combined dual-modality photodynamic therapy (PDT) and hypoxia-activated chemotherapy. Despite the current success in developing combined dual- or multi-modality cancer therapy, the absence of a facile method to optimize the ratio of therapeutic agents during multifunctional nanomedicine fabrication has impaired the clinical potential of combination therapy.

Studies have revealed that the ratio of therapeutic agents in co-delivery systems is vital to accomplish desired synergistic multi-modality cancer therapy [14,15]. Current strategies in optimizing the ratio of therapeutic agents often involve in tuning the feed ratio of drugs that are either physically absorbed into the nanocarriers or chemically polymerzied/conjugated to the backbone of polymers [16], [17], [18]. Due to the different physical property of therapeutic agents, the final ratio of co-loaded therapeutic agents in the obtained nanomedicine might be quite different from expectations, and the therapeutic agents might also suffer from premature release before reaching targeted tumor site [19]. In addition, simultaneously loading both hydrophilic and hydrophobic drugs into one nanocarrier is often difficult to realize. Therefore, chemically polymerizing therapeutic agents or conjugating them to the polymer chain has become a favorable method to optimize the ratio of therapeutic agents for synergistic combination cancer therapy. For instance, Yuan and coworkers reported the polymerization of curcumin and mitoxantrone using disulfide as a linker to fabricate GSH responsive dual-drug loaded nanomedicine for drug resistance reversal [20]. Dhar and coworkers developed a PLA-based biodegradable polymer with multiple terminal functionalities that can be conjuated with anti-inflammatory and chemotherapeutic agents (asprin and cisplatin) at a predefined ratio. The self-assembled nanomedicine with synergistic dual drugs exhibited incrased efficacy towards cisplatin resistant cancer [21]. Moreover, Qian and coworkers reported the covalent conjugation of chemotheraputic agent and photosensitizer to PEG chain with a predefined ratio of camptothecin and pyropheophorbide-a [22]. The resultant polymer self-assembled into a dual-modality anti-tumor nanomedicine for combined chemotherapy and PDT. However, chemical polymerization/conjugation methods often require premodification of all chemotherapeutic agents by functional group to cater for the polymer structure, which might intrude their pharmaceutical activity or bring unexpected side effects. Moreover, the syntheic procedures are often tedious and time-consuming. Therefore, a more facile and universal strategy to optimize the ratio of therapeutic agents during multimodal nanomedicine fabrication, ideally via ‘shake-and-serve’, is highly desired.

Macrocycle-based supramolecular recognition provides a facile approach to encapsulate various size-matched guest molecules into the intrinsic cavity of macrocycles in a spontaneous process. Upon inclusion by macrocycles, the bioavailability of the guest drug is improved and its nontarget toxicity is reduced [23]. The host-guest interaction between macrocycles and guest molecules is also an attractive driving force to build various biomaterials that are inherently stimuli-responsive via competitive binding by pathological stimuli [24,25]. Thus far, dual- or multi-modal supramolecular therapeutics have been developed through polymerization or covalent conjugation of macrocycle-based recognition motifs to diverse materials including polymers and inorganic materials [26], [27], [28], [29]. Cucurbit[7]uril (CB[7]), a macrocyclic host molecule composed of methylene bridged glycoluril, can include a wide range of pristine drugs with high affinity [30]. In this work, CB[7] was conjugated to the chain of hyaluronic acid to afford HA-CB[7] that can simultanously encapsulate adamantane-peglate modified photosensitizer Chlorin e6 (ADA-PEG-Ce6, APC) and the pristine chemotherapeutic agent oxaliplatin (OX) via host-guest complexation. The resultant HA-based supramolecular system could self-assemble into nanoparticles with CD44-targeting capability (OXHANPs) for combined dual-modality PDT and chemotherapy of cancer (Fig. 1). Particularly, due to the strong binding between CB[7] and the therapeutic agents, the ratio between OX and Ce6 could be readily optimized via host-guest complexation to realize synergistic effects. Atovaquone (Ato), a mitochondrial respiration inhibitor, was loaded into the optimized OXHANPs to relieve hypoxic tumor microenvironment, leading to an oxygen-economized PDT for further improving the therapeutic outcomes [31,32]. Using CB[7]-based host-guest complexation to facilely optimize the ratio of therapeutic agents could be expanded to diverse multi-modal supramolecular cancer nanomedicines.