Functional nanomaterials have attracted much attention due to the unique properties of these nanoconstructs. In recognition of the huge potential within this field, much research has been devoted to develop sophisticated nanoparticles for medical diagnostics, sensors, contrast agents, vaccines and drug delivery. The objective of this PhD thesis was to expand the field of liposomal drug delivery by developing novel methods to efficienctly functionalize and subsequently sensitize liposomes towards internal stimuli, such as matrix metalloproteinases. Initially, we investigated a novel method to post-functionalize and directly quantify the degree of conversion without prior purification. Based on Cu-free Click chemistry, quantitative conversion under very mild conditions was achieved using conditions which might be equally suited for other nanomaterials. Being able to rapidly determine ligand surface density after post-functionalization is highly important, to ensure batch-to-batch reproducibility and to ensure that the desired ligand surface density has been accomplished. A systematic study was furthermore conducted to elucidate the optimal post-functionalization chemistry, in addition to the importance of the relative position of the reactive functionalities. Surface conjugation reactions of octreotate by Michael addition, Click chemistry, Cu-free Click chemistry or oxime bond formation were investigated. From these studies it was evident that chemical reactions performed directly on the surface of functionalized liposomes were slower than the solution phase counterpart and often far from quantitative. The effect of active targeting with 64Cu octreotate liposomes targeting the somatostatin receptor 2 was evaluated to improve tumor bioimaging for diagnostic applications, using positron emission tomography. Targeted liposomes had a sufficient circulation profile to passively accumulate in tumor tissue of H727xenografts in nude mice, but no statistical difference was detected in the tumor accumulation compared to control-liposomes. Despite this, the tumor-to-muscle ratio for targeted liposomes was significantly higher than for the controlliposomes, which indicated that active targeting can improve tumor-to-muscle contrast, thus, improving bioimaging for diagnostic applications. Finally, a novel drug delivery system based on charge-triggering of matrix metalloproteinase 2/9 sensitive PEGylated lipopeptides was designed. Methods to efficiently synthesize conjugates with the lipid-peptide-PEG motif were developed, and the use of these conjugates to shield positively charged liposomeand lipoplex formulations were described. The synthesized conjugates efficiently shielded cationic charges present at the surface of the nanoconstructs, resulting in anionic nanoparticles with long circulation properties in xenograft HT1080 tumor‐bearing mice. Charge reversal by peptide hydrolysis was achieved in the presence of proteases, resulting in cationic particles which were readily internalized by cells in vitro. The use of matrix metalloproteinase sensitive liposomes and lipoplexes dramatically enhanced the cytotoxicity of known chemotherapeutics and facilitated effective gene transfection in vitro. Concluding on the work of this PhD thesis, we managed to expand the field of functional nanomaterials by developing novel methods to conjugate and directly quantify the surface density of immobilized ligands. Furthermore, a unique drug delivery system based on charge shielding and subsequent charge triggering by matrix metalloproteinase 2 has been established. This system is currently being further investigated in vivo, in order to test the therapeutic capacity of the system.